WO2020125659A1 - Compound for use in retinal diseases - Google Patents

Compound for use in retinal diseases Download PDF

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Publication number
WO2020125659A1
WO2020125659A1 PCT/CN2019/126178 CN2019126178W WO2020125659A1 WO 2020125659 A1 WO2020125659 A1 WO 2020125659A1 CN 2019126178 W CN2019126178 W CN 2019126178W WO 2020125659 A1 WO2020125659 A1 WO 2020125659A1
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compound
reaction
pharmaceutically acceptable
acceptable salt
synthesis
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PCT/CN2019/126178
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French (fr)
Chinese (zh)
Inventor
李鹏
李小林
罗志
贺海鹰
胡国平
黎健
陈曙辉
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南京明德新药研发有限公司
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Application filed by 南京明德新药研发有限公司 filed Critical 南京明德新药研发有限公司
Priority to MX2021007140A priority Critical patent/MX2021007140A/en
Priority to CN201980083959.7A priority patent/CN113227051B/en
Priority to AU2019409160A priority patent/AU2019409160B2/en
Priority to EP19901226.1A priority patent/EP3901138A4/en
Priority to JP2021535806A priority patent/JP7165270B2/en
Priority to US17/309,611 priority patent/US11932617B2/en
Priority to CA3123473A priority patent/CA3123473C/en
Priority to KR1020217022247A priority patent/KR102651579B1/en
Publication of WO2020125659A1 publication Critical patent/WO2020125659A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to an aldehyde binding agent, in particular to a compound represented by formula (II) or a pharmaceutically acceptable salt.
  • Xerophthalmia also known as xerokeratoconjunctivitis, refers to the abnormality of the quality or quantity of tear fluid or abnormal kinetics caused by any reason, which leads to a decrease in tear film stability and is accompanied by a variety of features of ocular discomfort (or) ocular surface tissue lesions
  • the general term for disease are: eye irritation, visual impairment and tear film instability. Some of this syndrome is caused by inflammation of the ocular surface, resulting in a loss of lacrimal gland function. In addition, it is also related to systemic autoimmunity.
  • aldehydes are produced in the body or eye tissues and organs through metabolic mechanisms, such as malondialdehyde (MDA), 4-hydroxy-2-nonenal (4HNE), etc.
  • MDA malondialdehyde
  • HNE 4-hydroxy-2-nonenal
  • NF-kappaB inflammatory molecular regulators
  • small molecule drugs enter eye inflammation sites in the form of eye drops or oral administration, and through complexing reactions with aldehydes in the body, thereby reducing aldehyde toxicity, reducing inflammation, and achieving the treatment of dry eye syndrome.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • T 1 , T 2 , T 3 and T 4 are independently selected from N, C and CR 1 ;
  • L is selected from single bonds, -O-, -S-, -NR 2 -and -(CR 3 R 4 ) n -;
  • Each R 1 is independently selected from H, F, Cl, Br, I, OH, and NH 2 ;
  • R 2 is selected from H and optionally substituted with 1,2 or 3 substituents R a is C 1-3 alkyl;
  • R 3 and R 4 are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2, or 3 R b ;
  • n is selected from 1, 2, and 3;
  • R a and R b are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and CH 3 .
  • R 2 is selected from H, CH 3 and CH 2 CH 3, and the CH 3 CH 2 CH 3 optionally substituted by 1, 2 or 3 R a, according to the present invention as other variables definition.
  • R 2 is selected from H, CH 3 and CH 2 CH 3 , and other variables are as defined in the present invention.
  • R 3 and R 4 are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 and CH 2 CH 3 , the CH 3 and CH 2 CH 3 is optionally substituted with 1, 2, or 3 R b , and other variables are as defined in the present invention.
  • R 3 and R 4 are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 and CH 2 CH 3 , and other variables are as defined in the present invention .
  • the aforementioned L is selected from single bonds, -O-, -S-, -NH-, -(CH 2 ) 2 -, and -CH 2 -, and other variables are as defined in the invention.
  • the present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
  • T 1 , T 2 , T 3 and T 4 are independently selected from N, C and CR 1 ;
  • T 6 is selected from C, CR 6 and N;
  • T 7 is selected from N and CR 7 ;
  • L is selected from single bonds, -O-, -S-, -NR 2 -and -(CR 3 R 4 ) n -;
  • Each R 1 is independently selected from H, F, Cl, Br, I, OH, and NH 2 ;
  • R 2 is selected from H and optionally substituted with 1,2 or 3 substituents R a is C 1-3 alkyl;
  • R 3 and R 4 are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2, or 3 R b ;
  • R 5, R 6 and R 7 are independently selected from H, F, Cl, Br and I;
  • n is selected from 1, 2, and 3;
  • R a and R b are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and CH 3 .
  • R 2 is selected from H, CH 3 and CH 2 CH 3, and the CH 3 CH 2 CH 3 optionally substituted by 1, 2 or 3 R a, according to the present invention as other variables definition.
  • R 2 is selected from H, CH 3 and CH 2 CH 3 , and other variables are as defined in the present invention.
  • R 3 and R 4 are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 and CH 2 CH 3 , the CH 3 and CH 2 CH 3 is optionally substituted with 1, 2, or 3 R b , and other variables are as defined in the present invention.
  • R 3 and R 4 are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 and CH 2 CH 3 , and other variables are as defined in the present invention .
  • the aforementioned L is selected from single bonds, -O-, -S-, -NH-, -(CH 2 ) 2 -, and -CH 2 -, and other variables are as defined in the invention.
  • the above compound or a pharmaceutically acceptable salt thereof is selected from
  • T 3 and T 4 are independently selected from N and CR 1 ;
  • R 1 and L are as defined in the present invention.
  • the above compound or a pharmaceutically acceptable salt thereof is selected from
  • R 1 and L are as defined in the present invention.
  • the present invention also provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof, which is selected from:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of a compound according to the above or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the use of the above compound or a pharmaceutically acceptable salt thereof or the above composition in the preparation of drugs related to aldehyde binding agents in some aspects of the present invention, the use of the above compound or a pharmaceutically acceptable salt thereof or the above composition in the preparation of drugs related to aldehyde binding agents.
  • the aforementioned application is characterized in that the aldehyde-binding agent-related drug is a drug for dry eye.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present invention, prepared from a compound having a specific substituent and a relatively non-toxic acid or base found in the present invention.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Bisulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid and other similar acids; also includes salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid. Certain compounds of the present invention contain basic and acidic functional groups and can be converted to any
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.
  • the compounds provided by the invention also exist in prodrug forms.
  • the prodrugs of the compounds described herein easily undergo chemical changes under physiological conditions to transform the compounds of the invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in the in vivo environment.
  • Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms.
  • the solvated form is equivalent to the unsolvated form, and is included in the scope of the present invention.
  • optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, where the resulting mixture of diastereomers is separated and the auxiliary groups are cleaved to provide pure The desired enantiomer.
  • a diastereomer salt is formed with an appropriate optically active acid or base, and then by conventional methods known in the art The diastereomers are resolved and the pure enantiomers are recovered.
  • the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography that uses a chiral stationary phase and is optionally combined with chemical derivatization methods (eg, amino groups from amines) Formate).
  • the compound of the present invention may contain unnatural proportions of atomic isotopes in one or more atoms constituting the compound.
  • compounds can be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • the hydrogen can be replaced by heavy hydrogen to form a deuterated drug.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
  • deuterated drugs have lower toxicity and increase drug stability. , Strengthen efficacy, prolong the biological half-life of drugs and other advantages.
  • the conversion of all isotopic compositions of the compounds of the present invention, whether radioactive or not, is included within the scope of the present invention.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include heavy hydrogen and hydrogen variants, as long as the valence state of the particular atom is normal and the compound after substitution is stable of.
  • Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary on the basis of chemical realization.
  • any variable (such as R) appears more than once in the composition or structure of a compound, its definition in each case is independent.
  • R in each case has independent options.
  • substituents and/or variants thereof are only allowed if such combinations will produce stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • one of the variables When one of the variables is selected from a single bond, it means that the two groups to which it is connected are directly connected. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
  • substituents listed do not indicate through which atom they are connected to the substituted group, such substituents can be bonded through any of their atoms, for example, pyridyl as a substituent can be through any one of the pyridine rings The carbon atom is attached to the substituted group.
  • connection direction is arbitrary, for example,
  • the linking group L in the middle is -MW-, then -MW- can be formed by connecting ring A and ring B in the same direction as the reading order from left to right It can also be formed by connecting ring A and ring B in the opposite direction to the reading order from left to right
  • Combinations of the linking group, substituents, and/or variants thereof are only allowed if such a combination will produce a stable compound.
  • C 1-6 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 6 carbon atoms.
  • the C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl groups; etc.; Is monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine).
  • C 1-6 alkyl examples include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl , S-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl and so on.
  • C 1-3 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it may be monovalent (such as methyl), divalent (such as methylene), or polyvalent (such as methine) .
  • Example C 1- 3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n- propyl and isopropyl) and the like.
  • C 1-3 alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms connected to the rest of the molecule by one oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like.
  • Examples of C 1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • C n-n+m or C n -C n+m includes any specific case of n to n+m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , and also includes any range from n to n+m, for example, C 1-12 includes C 1- 3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12, etc.; in the same way, n yuan to n +m member means that the number of atoms in the ring is n to n+m, for example, 3-12 member ring includes 3 member ring, 4 member ring, 5 member ring, 6 member ring, 7 member ring, 8 member ring, 9 member ring , 10-membered ring, 11-
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (eg, an affinity substitution reaction).
  • substituent groups include triflate; chlorine, bromine, and iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, and p-toluenesulfonate Ester, etc.; acyloxy, such as acetoxy, trifluoroacetoxy, etc.
  • protecting group includes but is not limited to "amino protecting group", “hydroxy protecting group” or “mercapto protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorene methoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-methoxyphenyl) methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldi
  • hydroxyl protecting group refers to a protecting group suitable for preventing side reactions of hydroxyl groups.
  • Representative hydroxy protecting groups include, but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanoyl groups (such as acetyl); arylmethyl groups, such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl, such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and so on.
  • alkyl groups such as methyl, ethyl, and tert-butyl
  • acyl groups such as alkanoyl groups (such as acetyl)
  • arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by the combination with other chemical synthesis methods and well known to those skilled in the art Equivalently, preferred embodiments include but are not limited to the embodiments of the present invention.
  • aq stands for water
  • HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride
  • m-CPBA stands for 3-chloroperoxybenzoic acid
  • eq stands for equivalent and equivalent
  • CDI stands for Carbonyldiimidazole
  • DCM for methylene chloride
  • PE PE
  • DIAD diisopropyl azodicarboxylate
  • DMF for N,N-dimethylformamide
  • DMSO for dimethyl sulfoxide
  • EtOAc for ethyl acetate
  • EtOH stands for ethanol
  • MeOH stands for methanol
  • CBz stands for benzyloxycarbonyl, which
  • Figure 2 Results of tear secretion in mice with dry eye syndrome
  • Figure 3 Results of corneal fluorescence staining of the mouse dry eye syndrome efficacy experiment.
  • the compound of the invention has better aldehyde complexing ability, which helps to relieve inflammation of the eye and achieve the purpose of treating dry eye.
  • Substrate 1-2 (200 mg, 605 ⁇ mol, 1 eq) was dissolved in tetrahydrofuran (20 mL), methyl magnesium bromide (3M, 4.04 mL, 20 eq) was slowly added dropwise at 0°C, and the reaction was stirred at 0°C 2 hour. Water (20 mL) was added to quench the reaction, then ethyl acetate (50 mL*3) was added for extraction, and the organic phase was concentrated. The mixture was dissolved in dimethylformamide (DMF) and purified by HPLC (neutral). Compound 1 is obtained.
  • DMF dimethylformamide
  • Dry eye syndrome is caused by inflammation inside the eye. These inflammations will produce some aldehydes in the body. If these aldehydes are not eliminated in time, they will accelerate the symptoms of inflammation and make dry eye syndrome worse.
  • a relatively superior compound is selected.
  • Sampling method Pipette gun to sample 25 microliters of the upper emulsified layer, 50 microliters of the lower aqueous phase, and dilute with 1 ml of methanol.
  • Nonanal has a weak UV absorption at a wavelength of 254 nm and has a small overall effect on the content of the complexed product. Therefore, the percentage of the complex at a high-performance liquid phase at 254 nm is compared to observe the aldehyde capture of the compound. ability. See Figure 1 and Table 1:
  • HPLC analysis method is XBRIGE 2.5 ⁇ m, 3.0*100mm 5-95CD_XBEH_12min_0.8.lcm or XBRIGE 2.5 ⁇ m, 3.0*100mm 5-80CD_XBEH_12min_0.8.lcm
  • the detection HPLC analysis method is XBRIGE 2.5 ⁇ m, 3.0*100mm 5-80CD_XBEH_12min_0.8.lcm,
  • Retention time 6.689 minutes; 6.787 minutes; 6.966 minutes; 7.102 minutes is the absorption peak of the product of complexing a molecule of aldehyde
  • the retention time is 8.905 minutes; 9.010 minutes; 9.075 minutes is the absorption peak of the bimolecular aldehyde complexed product.
  • Test purpose To study the inhibitory effect of compounds on human liver microsome cytochrome P450
  • Test process The compound's inhibitory study on human liver microsomal cytochrome P450 (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4), mixed human liver microsomes were selected as the source of CYP450 enzyme, and different concentrations of compounds (10,5 , 1.5, 0.5, 0.15, 0.05, 0.015 mM) were incubated with 5 probe substrates of CYP enzymes (including two substrates for CYP3A4) and cofactors (NADPH) to determine the compound’s IC for each CYP enzyme inhibition 50 value.
  • the test results are as follows:
  • the invention has high safety and low possibility of drug interaction.
  • the pharmacokinetic characteristics of rodents were intravenously tested using standard protocols.
  • the candidate compounds were formulated as clear solutions, and SD rats were given 20 mg/kg, which was given as a single intravenous injection for 5 consecutive days.
  • the intravenous injection solvent is 10% hydroxypropyl ⁇ cyclodextrin aqueous solution. Collect the whole blood samples at 0.033, 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after the first and fifth days of dosing, centrifuge at 3000r for 10 minutes, and separate the supernatant to obtain a plasma sample.
  • Plasma samples were mixed with 300 ⁇ L of acetonitrile solution containing internal standard precipitated protein, centrifuged to take 2 ⁇ L of supernatant for injection, quantitative analysis of blood drug concentration by LC-MS/MS analysis method, and calculation of pharmacokinetic parameters, such as clearance rate, half-life, drug time Area under the curve.
  • the compound of the present invention is administered by injection for 5 consecutive days without risk of drug accumulation.
  • the rodent pharmacokinetic characteristics of the compound after intravenous injection were tested in a standard protocol.
  • the candidate compound was formulated as a clear solution, and the beagle dog was given a single intravenous injection of 1 mg/kg.
  • the intravenous injection solvent is 10% hydroxypropyl ⁇ cyclodextrin aqueous solution.
  • the present invention has high clearance rate, moderate half-life, and good pharmacokinetic characteristics.
  • the standard protocol was used to test the pharmacokinetic characteristics of the compound in the monkey after intravenous injection.
  • the candidate compound was formulated as a clear solution, and the cynomolgus monkey was given a single intravenous injection of 1 mg/kg.
  • the intravenous injection solvent is 10% hydroxypropyl ⁇ cyclodextrin aqueous solution.
  • Plasma samples 20 ⁇ L of plasma sample and 400 ⁇ L of acetonitrile solution containing internal standard to precipitate protein Mix, centrifuge and take 2 ⁇ L of supernatant for injection, quantitatively analyze the blood drug concentration by LC-MS/MS analysis method, and calculate the pharmacokinetic parameters, such as clearance rate, half-life, area under the curve of drug time, etc.
  • the present invention has high clearance rate, moderate half-life, and good pharmacokinetic characteristics.
  • the candidate compound was formulated as a clear solution and administered to SD rats by eye drops.
  • the vehicle for eye drops is a 10% hydroxypropyl ⁇ cyclodextrin aqueous solution, and the drug concentration for eye drops is 5 mg/mL.
  • Corneal and whole blood were collected at 1 and 4 hours, respectively.
  • the cornea was homogenized with 15mM phosphate buffer (PBS): MeoH (2:1, v:v) buffer, and the whole blood sample was centrifuged at 3000r for 10 minutes to separate the supernatant plasma sample.
  • PBS phosphate buffer
  • test compounds 3, 7, 8 can enter the cornea by eye drop administration and have a drug effect.
  • the cornea/plasma of compound 3 is relatively high, the ratio is greater than 10, and the drug effect is on the cornea and target Good tropism.
  • Subcutaneous injection of scopolamine can induce dry eye syndrome in mice, and tear tear test and corneal fluorescence staining score examination can show reduced tear secretion and inflammation infiltration. And in the early stage of modeling, it can be predicted whether the model can reach the expected severity.
  • Day 7 and Day 12 performed tear test on all experimental animals and scored corneal fluorescence staining.
  • Corneal fluorescent staining scoring standard the animal cornea is divided into 5 regions, namely, upper, lower, nasal, temporal and central regions, each region is 0 to 3 points, each region is scored, the single eye score is The sum of the five regional scores. 0 points, no staining; 1 point, slight staining, dot-like staining and less than 5; 2 points, moderate staining, dot-like staining but no patchy staining; 3 points, heavy staining , Obvious fluorescent plaque.
  • Day 7 and Day 12 tear test tests for all laboratory animals are performed 30 minutes after the second administration, and Day 7 and Day 12 test corneal fluorescence staining scores for all laboratory animals must be performed 30 minutes after the third administration .

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Abstract

Provided is an aldehyde binder, specifically, disclosed is a compound as represented by formula (II) or a pharmaceutically acceptable salt.

Description

用于视网膜疾病的化合物Compounds for retinal diseases
相关申请的引用Citation of related applications
本申请主张如下优先权：This application claims the following priority:
CN201811550604.8，申请日2018-12-18；CN201811550604.8, application date 2018-12-18;
CN201911226373.X，申请日2019-12-04。CN201911226373.X, application date 2019-12-04.
技术领域Technical field
本发明涉及一种醛结合剂，具体涉及式(II)所示化合物或药学上可接受的盐。The present invention relates to an aldehyde binding agent, in particular to a compound represented by formula (II) or a pharmaceutically acceptable salt.
背景技术Background technique
干眼症又称角结膜干燥症，是指任何原因造成的泪液质或量异常或动力学异常，导致泪膜稳定性下降，并伴有眼部不适(或)眼表组织病变特征的多种疾病的总称。具体不适症状表现为：眼部刺激，视觉障碍和泪膜不稳定。这种综合症有的是由眼表炎症引起，导致泪腺功能缺失。此外，它也与***性自身免疫有关。Xerophthalmia, also known as xerokeratoconjunctivitis, refers to the abnormality of the quality or quantity of tear fluid or abnormal kinetics caused by any reason, which leads to a decrease in tear film stability and is accompanied by a variety of features of ocular discomfort (or) ocular surface tissue lesions The general term for disease. The specific symptoms of discomfort are: eye irritation, visual impairment and tear film instability. Some of this syndrome is caused by inflammation of the ocular surface, resulting in a loss of lacrimal gland function. In addition, it is also related to systemic autoimmunity.
由于体内或眼部组织器官通过代谢机制等产生一些有毒的醛，比如丙二醛(MDA)、4-羟基-2-壬烯醛(4HNE)等，这些醛类与蛋白质、碳水化合物、油脂和DNA高度反应，导致化学修饰生物分子，激活炎症分子调节物如NF-kappaB,从而促使不同器官受损，这是干眼症诱因之一。Because some toxic aldehydes are produced in the body or eye tissues and organs through metabolic mechanisms, such as malondialdehyde (MDA), 4-hydroxy-2-nonenal (4HNE), etc. These aldehydes are associated with proteins, carbohydrates, oils and DNA is highly responsive, leading to chemical modification of biological molecules and activation of inflammatory molecular regulators such as NF-kappaB, which promotes damage to different organs. This is one of the causes of dry eye syndrome.
本发明通过研究，小分子药物以滴眼或口服形式进入眼部炎症部位，通过与体内醛络合反应，从而降低醛毒性，降低炎症，达到治疗干眼症作用。According to the present invention, small molecule drugs enter eye inflammation sites in the form of eye drops or oral administration, and through complexing reactions with aldehydes in the body, thereby reducing aldehyde toxicity, reducing inflammation, and achieving the treatment of dry eye syndrome.
发明内容Summary of the invention
本发明提供了式(I)所示化合物或其药学上可接受的盐，The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2019126178-appb-000001
Figure PCTCN2019126178-appb-000001
其中，among them,
T 1、T 2、T 3和T 4分别独立地选自N、C和CR 1； T 1 , T 2 , T 3 and T 4 are independently selected from N, C and CR 1 ;
L选自单键、-O-、-S-、-NR 2-和-(CR 3R 4) n-； L is selected from single bonds, -O-, -S-, -NR 2 -and -(CR 3 R 4 ) n -;
各R 1分别独立地选自H、F、Cl、Br、I、OH和NH 2； Each R 1 is independently selected from H, F, Cl, Br, I, OH, and NH 2 ;
R 2选自H和任选被1、2或3个R a取代的C 1-3烷基； R 2 is selected from H and optionally substituted with 1,2 or 3 substituents R a is C 1-3 alkyl;
R 3和R 4分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和任选被1、2或3个R b取代的C 1-3烷基； R 3 and R 4 are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2, or 3 R b ;
n选自1、2和3；n is selected from 1, 2, and 3;
R a和R b分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和CH 3。 R a and R b are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and CH 3 .
本发明的一些方案中，上述R 2选自H、CH 3和CH 2CH 3，所述CH 3和CH 2CH 3任选被1、2或3个R a取代，其他变量如本发明所定义。 Some aspects of the present invention, the above-described R 2 is selected from H, CH 3 and CH 2 CH 3, and the CH 3 CH 2 CH 3 optionally substituted by 1, 2 or 3 R a, according to the present invention as other variables definition.
本发明的一些方案中，上述R 2选自H、CH 3和CH 2CH 3，其他变量如本发明所定义。 In some aspects of the present invention, the above R 2 is selected from H, CH 3 and CH 2 CH 3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述R 3和R 4分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3和CH 2CH 3，所述CH 3和CH 2CH 3任选被1、2或3个R b取代，其他变量如本发明所定义。 In some aspects of the present invention, the above R 3 and R 4 are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 and CH 2 CH 3 , the CH 3 and CH 2 CH 3 is optionally substituted with 1, 2, or 3 R b , and other variables are as defined in the present invention.
本发明的一些方案中，上述R 3和R 4分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3和CH 2CH 3，其他变量如本发明所定义。 In some aspects of the present invention, the above R 3 and R 4 are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 and CH 2 CH 3 , and other variables are as defined in the present invention .
本发明的一些方案中，上述L选自单键、-O-、-S-、-NH-、-(CH 2) 2-和-CH 2-，其他变量如本发明所定义。 In some aspects of the invention, the aforementioned L is selected from single bonds, -O-, -S-, -NH-, -(CH 2 ) 2 -, and -CH 2 -, and other variables are as defined in the invention.
本发明提供了式(II)所示化合物或其药学上可接受的盐，The present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2019126178-appb-000002
Figure PCTCN2019126178-appb-000002
其中，among them,
Figure PCTCN2019126178-appb-000003
选自单键和双键；
Figure PCTCN2019126178-appb-000003
Choose from single and double bonds;
T 1、T 2、T 3和T 4分别独立地选自N、C和CR 1； T 1 , T 2 , T 3 and T 4 are independently selected from N, C and CR 1 ;
T 5选自C、CR 5和C＝O； T 5 is selected from C, CR 5 and C=O;
T 6选自C、CR 6和N； T 6 is selected from C, CR 6 and N;
T 7选自N和CR 7； T 7 is selected from N and CR 7 ;
当T 5选自C＝O，T 6选自N时，
Figure PCTCN2019126178-appb-000004
选自单键； When T 5 is selected from C=O and T 6 is selected from N,
Figure PCTCN2019126178-appb-000004
Selected from single bonds;
L选自单键、-O-、-S-、-NR 2-和-(CR 3R 4) n-； L is selected from single bonds, -O-, -S-, -NR 2 -and -(CR 3 R 4 ) n -;
各R 1分别独立地选自H、F、Cl、Br、I、OH和NH 2； Each R 1 is independently selected from H, F, Cl, Br, I, OH, and NH 2 ;
R 2选自H和任选被1、2或3个R a取代的C 1-3烷基； R 2 is selected from H and optionally substituted with 1,2 or 3 substituents R a is C 1-3 alkyl;
R 3和R 4分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和任选被1、2或3个R b取代的C 1-3烷基； R 3 and R 4 are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2, or 3 R b ;
R 5、R 6和R 7分别独立地选自H、F、Cl、Br和I； R 5, R 6 and R 7 are independently selected from H, F, Cl, Br and I;
n选自1、2和3；n is selected from 1, 2, and 3;
R a和R b分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和CH 3。 R a and R b are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and CH 3 .
本发明的一些方案中，上述R 2选自H、CH 3和CH 2CH 3，所述CH 3和CH 2CH 3任选被1、2或3个R a取代，其他变量如本发明所定义。 Some aspects of the present invention, the above-described R 2 is selected from H, CH 3 and CH 2 CH 3, and the CH 3 CH 2 CH 3 optionally substituted by 1, 2 or 3 R a, according to the present invention as other variables definition.
本发明的一些方案中，上述R 2选自H、CH 3和CH 2CH 3，其他变量如本发明所定义。 In some aspects of the present invention, the above R 2 is selected from H, CH 3 and CH 2 CH 3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述R 3和R 4分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3和CH 2CH 3，所述CH 3和CH 2CH 3任选被1、2或3个R b取代，其他变量如本发明所定义。 In some aspects of the present invention, the above R 3 and R 4 are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 and CH 2 CH 3 , the CH 3 and CH 2 CH 3 is optionally substituted with 1, 2, or 3 R b , and other variables are as defined in the present invention.
本发明的一些方案中，上述R 3和R 4分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3和CH 2CH 3，其他变量如本发明所定义。 In some aspects of the present invention, the above R 3 and R 4 are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 and CH 2 CH 3 , and other variables are as defined in the present invention .
本发明的一些方案中，上述L选自单键、-O-、-S-、-NH-、-(CH 2) 2-和-CH 2-，其他变量如本发明所定义。 In some aspects of the invention, the aforementioned L is selected from single bonds, -O-, -S-, -NH-, -(CH 2 ) 2 -, and -CH 2 -, and other variables are as defined in the invention.
本发明还有一些方案是由上述各变量任意组合而来。There are still some solutions of the present invention that are derived from any combination of the above variables.
本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自In some embodiments of the present invention, the above compound or a pharmaceutically acceptable salt thereof is selected from
Figure PCTCN2019126178-appb-000005
Figure PCTCN2019126178-appb-000005
其中，among them,
T 3、T 4分别独立地选自N和CR 1； T 3 and T 4 are independently selected from N and CR 1 ;
R 1和L如本发明所定义。 R 1 and L are as defined in the present invention.
本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自In some embodiments of the present invention, the above compound or a pharmaceutically acceptable salt thereof is selected from
Figure PCTCN2019126178-appb-000006
Figure PCTCN2019126178-appb-000006
其中，among them,
R 1和L如本发明所定义。 R 1 and L are as defined in the present invention.
本发明还提供了下式所示化合物或其药学上可接受的盐，其选自：The present invention also provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof, which is selected from:
Figure PCTCN2019126178-appb-000007
Figure PCTCN2019126178-appb-000007
本发明还提供了一种药物组合物，包括作为活性成分的治疗有效量的根据上述的化合物或其药学上可接受的盐以及药学上可接受的载体。The present invention also provides a pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of a compound according to the above or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
本发明的一些方案中，上述化合物或其药学上可接受的盐或者上述的组合物在制备醛结合剂相关药物上的应用。In some aspects of the present invention, the use of the above compound or a pharmaceutically acceptable salt thereof or the above composition in the preparation of drugs related to aldehyde binding agents.
本发明的一些方案中，上述的应用，其特征在于，所述醛结合剂相关药物是用于干眼症的药物。In some aspects of the present invention, the aforementioned application is characterized in that the aldehyde-binding agent-related drug is a drug for dry eye.
定义和说明Definition and description
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A specific term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding trade product or its active ingredient. The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms, which are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, prepared from a compound having a specific substituent and a relatively non-toxic acid or base found in the present invention. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Bisulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid and other similar acids; also includes salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid. Certain compounds of the present invention contain basic and acidic functional groups and can be converted to any base or acid addition salt.
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。In addition to salt forms, the compounds provided by the invention also exist in prodrug forms. The prodrugs of the compounds described herein easily undergo chemical changes under physiological conditions to transform the compounds of the invention. In addition, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in the in vivo environment.
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms. Generally speaking, the solvated form is equivalent to the unsolvated form, and is included in the scope of the present invention.
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过 本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。 The optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, where the resulting mixture of diastereomers is separated and the auxiliary groups are cleaved to provide pure The desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomer salt is formed with an appropriate optically active acid or base, and then by conventional methods known in the art The diastereomers are resolved and the pure enantiomers are recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography that uses a chiral stationary phase and is optionally combined with chemical derivatization methods (eg, amino groups from amines) Formate). The compound of the present invention may contain unnatural proportions of atomic isotopes in one or more atoms constituting the compound. For example, compounds can be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). For another example, the hydrogen can be replaced by heavy hydrogen to form a deuterated drug. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have lower toxicity and increase drug stability. , Strengthen efficacy, prolong the biological half-life of drugs and other advantages. The conversion of all isotopic compositions of the compounds of the present invention, whether radioactive or not, is included within the scope of the present invention.
术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。The term "optional" or "optionally" means that the subsequently described event or condition may, but need not necessarily occur, and that the description includes situations where the event or condition occurs and circumstances where the event or condition does not occur .
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include heavy hydrogen and hydrogen variants, as long as the valence state of the particular atom is normal and the compound after substitution is stable of. When the substituent is oxygen (ie = O), it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary on the basis of chemical realization.
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When any variable (such as R) appears more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group can optionally be substituted with at most two Rs, and R in each case has independent options. Furthermore, combinations of substituents and/or variants thereof are only allowed if such combinations will produce stable compounds.
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。 When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。When one of the variables is selected from a single bond, it means that the two groups to which it is connected are directly connected. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
Figure PCTCN2019126178-appb-000008
中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成
Figure PCTCN2019126178-appb-000009
也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成
Figure PCTCN2019126178-appb-000010
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。 When a substituent is vacant, it means that the substituent does not exist. For example, when X is vacant in AX, it means that the structure is actually A. When the substituents listed do not indicate through which atom they are connected to the substituted group, such substituents can be bonded through any of their atoms, for example, pyridyl as a substituent can be through any one of the pyridine rings The carbon atom is attached to the substituted group. When the listed linking group does not indicate the connection direction, the connection direction is arbitrary, for example,
Figure PCTCN2019126178-appb-000008
The linking group L in the middle is -MW-, then -MW- can be formed by connecting ring A and ring B in the same direction as the reading order from left to right
Figure PCTCN2019126178-appb-000009
It can also be formed by connecting ring A and ring B in the opposite direction to the reading order from left to right
Figure PCTCN2019126178-appb-000010
Combinations of the linking group, substituents, and/or variants thereof are only allowed if such a combination will produce a stable compound.
除非另有规定，术语“C 1-6烷基”用于表示直链或支链的由1至6个碳原子组成的饱和碳氢基团。所述C 1-6烷基包括C 1-5、C 1-4、C 1-3、C 1-2、C 2-6、C 2-4、C 6和C 5烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1-6烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)、丁基(包括n-丁基，异丁基，s-丁基和t-丁基)、戊基(包括n-戊基，异戊基和新戊基)、己基等。 Unless otherwise specified, the term "C 1-6 alkyl" is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 6 carbon atoms. The C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl groups; etc.; Is monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine). Examples of C 1-6 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl , S-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl and so on.
除非另有规定，术语“C 1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C 1-3烷基包括C 1-2和C 2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1- 3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。 Unless otherwise specified, the term "C 1-3 alkyl" is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 3 carbon atoms. The C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it may be monovalent (such as methyl), divalent (such as methylene), or polyvalent (such as methine) . Example C 1- 3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n- propyl and isopropyl) and the like.
除非另有规定，术语“C 1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C 1-3烷氧基包括C 1-2、C 2-3、C 3和C 2烷氧基等。C 1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。 Unless otherwise specified, the term "C 1-3 alkoxy" refers to those alkyl groups containing 1 to 3 carbon atoms connected to the rest of the molecule by one oxygen atom. The C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like. Examples of C 1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
除非另有规定，C n-n+m或C n-C n+m包括n至n+m个碳的任何一种具体情况，例如C 1-12包括C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11、和C 12，也包括n至n+m中的任何一个范围，例如C 1-12包括C 1- 3、C 1-6、C 1-9、C 3-6、C 3-9、C 3-12、C 6-9、C 6-12、和C 9-12等；同理，n元至n+m元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。 Unless otherwise specified, C n-n+m or C n -C n+m includes any specific case of n to n+m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , and also includes any range from n to n+m, for example, C 1-12 includes C 1- 3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12, etc.; in the same way, n yuan to n +m member means that the number of atoms in the ring is n to n+m, for example, 3-12 member ring includes 3 member ring, 4 member ring, 5 member ring, 6 member ring, 7 member ring, 8 member ring, 9 member ring , 10-membered ring, 11-membered ring, and 12-membered ring, also including any range from n to n+m, for example, 3-12 membered ring includes 3-6 membered ring, 3-9 membered ring, 5-6 membered ring Rings, 5-7 member rings, 6-7 member rings, 6-8 member rings, 6-10 member rings, etc.
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲和取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (eg, an affinity substitution reaction). For example, representative leaving groups include triflate; chlorine, bromine, and iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, and p-toluenesulfonate Ester, etc.; acyloxy, such as acetoxy, trifluoroacetoxy, etc.
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。The term "protecting group" includes but is not limited to "amino protecting group", "hydroxy protecting group" or "mercapto protecting group". The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorene methoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-methoxyphenyl) methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc. The term "hydroxyl protecting group" refers to a protecting group suitable for preventing side reactions of hydroxyl groups. Representative hydroxy protecting groups include, but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanoyl groups (such as acetyl); arylmethyl groups, such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl, such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and so on.
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by the combination with other chemical synthesis methods and well known to those skilled in the art Equivalently, preferred embodiments include but are not limited to the embodiments of the present invention.
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：aq代表水；HATU代表O-(7-氮杂苯并 ***-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表PE；DIAD代表偶氮二羧酸二异丙酯；DMF代表N,N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁氧羰基是一种胺保护基团；HOAc代表乙酸；NaCNBH 3代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc 2O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；SOCl 2代表氯化亚砜；CS 2代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺；NCS代表N-氯代丁二酰亚胺；n-Bu 4NF代表氟化四丁基铵；iPrOH代表2-丙醇；mp代表熔点；LDA代表二异丙基胺基锂；LiHMDS代表六甲基二硅基胺基锂；Xantphos代表4,5-双二苯基膦-9,9-二甲基氧杂蒽；LiAlH 4代表四氢铝锂；Pd(dba) 2代表三(二亚苄基丙酮)二钯；mCPBA代表间氯过氧苯甲酸；pd(dppf)Cl 2代表[1,1'-双(二苯基膦基)二茂铁]二氯化钯；DBU代表1,8-二氮杂双环[5.4.0]十一碳-7-烯。 The solvent used in the present invention is commercially available. This invention uses the following abbreviations: aq stands for water; HATU stands for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent and equivalent; CDI stands for Carbonyldiimidazole; DCM for methylene chloride; PE for PE; DIAD for diisopropyl azodicarboxylate; DMF for N,N-dimethylformamide; DMSO for dimethyl sulfoxide; EtOAc for ethyl acetate ; EtOH stands for ethanol; MeOH stands for methanol; CBz stands for benzyloxycarbonyl, which is an amine protecting group; BOC stands for tert-butoxycarbonyl, which is an amine protecting group; HOAc stands for acetic acid; NaCNBH 3 stands for sodium cyanoborohydride; rt represents room temperature; O/N represents overnight; THF represents tetrahydrofuran; Boc 2 O represents di-tert-butyl dicarbonate; TFA represents trifluoroacetic acid; DIPEA represents diisopropylethylamine; SOCl 2 represents sulfoxide chloride ; CS 2 stands for carbon disulfide; TsOH stands for p-toluenesulfonic acid; NFSI stands for N-fluoro-N-(benzenesulfonyl)benzenesulfonamide; NCS stands for N-chlorosuccinimide; n-Bu 4 NF stands for fluorinated Tetrabutylammonium; iPrOH stands for 2-propanol; mp stands for melting point; LDA stands for lithium diisopropylamide; LiHMDS stands for lithium hexamethyldisilazide; Xantphos stands for 4,5-bisdiphenylphosphine- 9,9-dimethyl xanthene; LiAlH 4 stands for lithium aluminum hydride; Pd(dba) 2 stands for tri(dibenzylideneacetone) dipalladium; mCPBA stands for m-chloroperoxybenzoic acid; pd(dppf)Cl 2 represents [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; DBU represents 1,8-diazabicyclo[5.4.0]undec-7-ene.
化合物依据本领域常规命名原则或者使用
Figure PCTCN2019126178-appb-000011
软件命名，市售化合物采用供应商目录名称。 Compounds are used according to conventional naming principles in the art or used
Figure PCTCN2019126178-appb-000011
The software is named, and the commercially available compounds adopt the supplier catalog name.
附图说明BRIEF DESCRIPTION
图1：体外醛捕捉能力测试结果；Figure 1: In vitro aldehyde capture ability test results;
图2：小鼠干眼症药效实验泪液分泌量结果；Figure 2: Results of tear secretion in mice with dry eye syndrome;
图3：小鼠干眼症药效实验角膜荧光染色结果。Figure 3: Results of corneal fluorescence staining of the mouse dry eye syndrome efficacy experiment.
技术效果Technical effect
本发明化合物具有较优的醛络合能力，有助于缓解眼部炎症，达到治疗干眼症的目的。The compound of the invention has better aldehyde complexing ability, which helps to relieve inflammation of the eye and achieve the purpose of treating dry eye.
具体实施方式detailed description
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。The present invention will be described in detail by the following examples, but it does not mean any disadvantageous limitation of the present invention. The present invention has been described in detail herein, and the specific embodiments thereof are also disclosed. For those skilled in the art, various changes and improvements are made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention Will be obvious.
实施例1：化合物1的合成Example 1: Synthesis of Compound 1
Figure PCTCN2019126178-appb-000012
Figure PCTCN2019126178-appb-000012
化合物1的合成路线：Synthetic route of compound 1:
Figure PCTCN2019126178-appb-000013
Figure PCTCN2019126178-appb-000013
步骤1：化合物1-2的合成Step 1: Synthesis of Compound 1-2
Figure PCTCN2019126178-appb-000014
Figure PCTCN2019126178-appb-000014
将化合物1-1(1.5g,6.12mmol,1eq)，六甲基二锡(1.60g,4.90mmol,1.02mL,0.8eq)和二三叔丁基磷钯(938.39mg,1.84mmol,0.3eq)溶于甲苯(20mL)，在80℃下搅拌14小时。TLC点板(二氯甲烷：甲醇＝10:1)检测反应完全，直接浓缩拌样。用快速硅胶柱纯化(流动相：0～10％二氯甲烷/甲醇)。得到化合物1-2。[M+1] +＝330.9 Compound 1-1 (1.5g, 6.12mmol, 1eq), hexamethylditin (1.60g, 4.90mmol, 1.02mL, 0.8eq) and ditri-tert-butylphospho-palladium (938.39mg, 1.84mmol, 0.3eq ) Was dissolved in toluene (20 mL) and stirred at 80°C for 14 hours. TLC spot plate (dichloromethane: methanol = 10:1) to detect the completion of the reaction, directly concentrate and mix samples. Purified with a flash silica gel column (mobile phase: 0-10% dichloromethane/methanol). Compound 1-2 is obtained. [M+1] + = 330.9
步骤2：化合物1的合成Step 2: Synthesis of Compound 1
Figure PCTCN2019126178-appb-000015
Figure PCTCN2019126178-appb-000015
将底物1-2(200mg,605μmol,1eq)溶于四氢呋喃(20mL)中，在0℃下慢慢滴加甲基溴化镁(3M,4.04mL,20eq)，反应在0℃下搅拌2小时。加水(20mL)淬灭反应，再加入乙酸乙酯(50mL*3)萃取，有机相浓缩。将混合物用二甲基甲酰胺(DMF)溶解送HPLC(中性)纯化。得到化合物1。Substrate 1-2 (200 mg, 605 μmol, 1 eq) was dissolved in tetrahydrofuran (20 mL), methyl magnesium bromide (3M, 4.04 mL, 20 eq) was slowly added dropwise at 0°C, and the reaction was stirred at 0°C 2 hour. Water (20 mL) was added to quench the reaction, then ethyl acetate (50 mL*3) was added for extraction, and the organic phase was concentrated. The mixture was dissolved in dimethylformamide (DMF) and purified by HPLC (neutral). Compound 1 is obtained.
1H NMR(400MHz,DMSO-d 6)δ7.80(d,J＝8.3Hz,2H),7.00(d,J＝8.3Hz,2H),5.56(s,4H),5.47(s,2H),1.56(s,12H)；LCMS:[M+H] +＝302.9 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.80 (d, J = 8.3 Hz, 2H), 7.00 (d, J = 8.3 Hz, 2H), 5.56 (s, 4H), 5.47 (s, 2H) , 1.56 (s, 12H); LCMS: [M+H] + = 302.9
实施例2：化合物2的合成Example 2: Synthesis of Compound 2
Figure PCTCN2019126178-appb-000016
Figure PCTCN2019126178-appb-000016
化合物2的合成路线:Synthetic route of compound 2:
Figure PCTCN2019126178-appb-000017
Figure PCTCN2019126178-appb-000017
步骤1：化合物2-3的合成Step 1: Synthesis of compound 2-3
Figure PCTCN2019126178-appb-000018
Figure PCTCN2019126178-appb-000018
将底物2-1(702.07mg,2.55mmol,1.5eq)和2-2(310mg,1.70mmol,1eq)溶于乙腈(20mL)中，再加入碳酸铯(1.11g,3.40mmol,2eq)，反应在50℃下搅拌3小时。反应结束后，将反应液直接过滤，滤液旋干，得到粗品。粗品用快速硅胶柱纯化(石油醚：乙酸乙酯＝100:0～60:40)。得到化合物2-3。The substrate 2-1 (702.07mg, 2.55mmol, 1.5eq) and 2-2 (310mg, 1.70mmol, 1eq) were dissolved in acetonitrile (20mL), and then added cesium carbonate (1.11g, 3.40mmol, 2eq), The reaction was stirred at 50°C for 3 hours. After the reaction, the reaction solution was directly filtered, and the filtrate was spin-dried to obtain a crude product. The crude product was purified with a flash silica gel column (petroleum ether: ethyl acetate = 100:0 ~ 60:40). Compound 2-3 is obtained.
1H NMR(400MHz,CDCl 3)δ8.42(d,J＝9.03Hz,1H),7.24(d,J＝4.02Hz,1H),7.15-7.20(m,1H),7.07-7.13(m,1H),5.82(br s,2H),4.39(dq,J＝4.27,7.11Hz,4H),1.35(td,J＝7.15,18.57Hz,6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.42 (d, J = 9.03 Hz, 1H), 7.24 (d, J = 4.02 Hz, 1H), 7.15-7.20 (m, 1H), 7.07-7.13 (m, 1H), 5.82 (br s, 2H), 4.39 (dq, J = 4.27, 7.11 Hz, 4H), 1.35 (td, J = 7.15, 18.57 Hz, 6H).
步骤2：化合物2-4的合成Step 2: Synthesis of compound 2-4
Figure PCTCN2019126178-appb-000019
Figure PCTCN2019126178-appb-000019
将化合物2-3(360mg,956.63μmol,1eq)，盐酸(12M,478.32μL,6eq)溶于乙醇(20mL)和水(5mL)中，加入还原铁粉(534.23mg,9.57mmol,10eq)，在25℃下搅拌2小时。反应结束后，反应液通过饱和碳酸钠水溶液(30mL)调节pH至9，再加入乙酸乙酯(30mL*2)萃取。有机相合并后，用无水硫酸钠干燥，旋干，得到粗品。粗品用快速硅胶柱纯化(石油醚：乙酸乙酯＝100:0～40:60)。得到化合物2-4。Compound 2-3 (360 mg, 956.63 μmol, 1 eq), hydrochloric acid (12M, 478.32 μL, 6 eq) were dissolved in ethanol (20 mL) and water (5 mL), and reduced iron powder (534.23 mg, 9.57 mmol, 10 eq) was added, Stir at 25°C for 2 hours. After the reaction was completed, the reaction solution was adjusted to pH 9 with a saturated sodium carbonate aqueous solution (30 mL), and ethyl acetate (30 mL*2) was added for extraction. After the organic phases are combined, dried with anhydrous sodium sulfate and spin-dried to obtain a crude product. The crude product was purified with a flash silica gel column (petroleum ether: ethyl acetate = 100:0 ~ 40:60). Compound 2-4 is obtained.
1H NMR(400MHz,CDCl 3)δ7.17-7.24(m,2H),7.09-7.16(m,2H),5.64(br s,4H),4.37(q,J＝7.03Hz,4H),1.37(t,J＝7.03Hz,6H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.17-7.24 (m, 2H), 7.09-7.16 (m, 2H), 5.64 (br s, 4H), 4.37 (q, J = 7.03 Hz, 4H), 1.37 (t, J = 7.03 Hz, 6H).
步骤3：化合物2的合成Step 3: Synthesis of Compound 2
Figure PCTCN2019126178-appb-000020
Figure PCTCN2019126178-appb-000020
将化合物2-4(120mg,346.48μmol,1eq)溶于四氢呋喃(10mL)中，冷却到0℃。在0℃下，滴加甲基溴化镁(3M,3.00mL,26eq)的2-甲基四氢呋喃溶液。反应在0℃下搅拌30分钟，再在25℃下搅拌2小时。反应结束后，加入饱和氯化铵水溶液(40mL)淬灭反应，再用乙酸乙酯(100mL)萃取。有机相用无水硫酸钠干燥，旋干，得到粗品。粗品通过HPLC分离(柱子型号:Waters Xbridge 150*25mm 5μm；流动相:[水(10mM碳酸氢铵溶液)-乙腈]；B(乙腈)％:0％-50％,10min)纯化，得到化合物2。Compound 2-4 (120 mg, 346.48 μmol, 1 eq) was dissolved in tetrahydrofuran (10 mL) and cooled to 0°C. At 0°C, a solution of methyl magnesium bromide (3M, 3.00 mL, 26 eq) in 2-methyltetrahydrofuran was added dropwise. The reaction was stirred at 0°C for 30 minutes and then at 25°C for 2 hours. After the reaction was completed, saturated aqueous ammonium chloride solution (40 mL) was added to quench the reaction, and extracted with ethyl acetate (100 mL). The organic phase was dried with anhydrous sodium sulfate and spin-dried to obtain a crude product. The crude product was separated by HPLC (column model: Waters Xbridge 150*25mm 5μm; mobile phase: [water (10mM ammonium bicarbonate solution)-acetonitrile]; B (acetonitrile)%: 0%-50%, 10min) to obtain compound 2 .
LCMS:[MS+H +]＝318.9. LCMS: [MS+H + ] = 318.9.
1H NMR(400MHz,DMSO-d 6)δ7.03(d,J＝8.28Hz,2H),6.57(d,J＝8.53Hz,2H),5.37(s,2H),5.27(s,4H),1.38(s,12H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.03 (d, J = 8.28 Hz, 2H), 6.57 (d, J = 8.53 Hz, 2H), 5.37 (s, 2H), 5.27 (s, 4H) , 1.38 (s, 12H).
实施例3：化合物3的合成Example 3: Synthesis of Compound 3
Figure PCTCN2019126178-appb-000021
Figure PCTCN2019126178-appb-000021
化合物3的合成路线:Synthetic route of compound 3:
Figure PCTCN2019126178-appb-000022
Figure PCTCN2019126178-appb-000022
步骤1：化合物3-3的合成Step 1: Synthesis of compound 3-3
Figure PCTCN2019126178-appb-000023
Figure PCTCN2019126178-appb-000023
将化合物3-1(300mg,1.30mmol,1eq)，3-2(379.73mg,1.69mmol,1.3eq)，磷酸钾(551.24mg,2.60mmol,2eq)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯.二氯甲烷(530.18mg,649.22μmol,0.5eq)溶于二氯乙烷 (15mL)，在80℃下搅拌15小时。反应结束后，反应液直接过滤，滤液旋干，得到粗品。粗品用快速硅胶柱(石油醚：乙酸乙酯＝100:0～50:50)纯化。得到化合物3-3。Compound 3-1 (300mg, 1.30mmol, 1eq), 3-2 (379.73mg, 1.69mmol, 1.3eq), potassium phosphate (551.24mg, 2.60mmol, 2eq) and [1,1'-bis(diphenyl Phosphinyl)ferrocene]palladium dichloride. dichloromethane (530.18 mg, 649.22 μmol, 0.5 eq) was dissolved in dichloroethane (15 mL) and stirred at 80° C. for 15 hours. After the reaction, the reaction solution was directly filtered, and the filtrate was spin-dried to obtain a crude product. The crude product was purified with a flash silica gel column (petroleum ether: ethyl acetate = 100:0 to 50:50). Compound 3-3 is obtained.
1H NMR(400MHz,CDCl 3)δ8.29(s,1H),8.08(s,1H),7.88(s,2H),7.25(s,1H),5.95(br s,2H),4.03(s,3H),3.96(s,3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.29 (s, 1H), 8.08 (s, 1H), 7.88 (s, 2H), 7.25 (s, 1H), 5.95 (br s, 2H), 4.03 (s , 3H), 3.96 (s, 3H).
步骤2：化合物3-4的合成Step 2: Synthesis of compound 3-4
Figure PCTCN2019126178-appb-000024
Figure PCTCN2019126178-appb-000024
将3-3(250mg,754.65μmol,1eq)，盐酸(12M,1.26mL,20eq)溶于甲醇(12mL)和水(3mL)中，加入还原铁粉(421.43mg,7.55mmol,10eq)，在25℃下搅拌1天15小时。反应结束后，反应液通过饱和碳酸钠水溶液(50mL)调节PH至9，再加入乙酸乙酯(60mL*2)萃取。有机相合并后，用无水硫酸钠干燥，旋干，得到粗品。粗品用快速硅胶柱纯化(石油醚：乙酸乙酯＝100:0～50:50)。得到化合物3-4。Dissolve 3-3 (250mg, 754.65μmol, 1eq), hydrochloric acid (12M, 1.26mL, 20eq) in methanol (12mL) and water (3mL), add reduced iron powder (421.43mg, 7.55mmol, 10eq), in Stir at 25°C for 1 day and 15 hours. After the reaction was completed, the reaction solution was adjusted to pH 9 with saturated sodium carbonate aqueous solution (50 mL), and ethyl acetate (60 mL*2) was added for extraction. After the organic phases are combined, dried with anhydrous sodium sulfate and spin-dried to obtain a crude product. The crude product was purified with a flash silica gel column (petroleum ether: ethyl acetate = 100:0 to 50:50). Compound 3-4 is obtained.
1H NMR(400MHz,DMSO-d 6)δ8.09(d,J＝2.01Hz,1H),7.82(d,J＝8.28Hz,1H),7.43(d,J＝2.01Hz,1H),7.08(d,J＝1.51Hz,1H),6.71-6.86(m,5H),3.83(d,J＝5.77Hz,6H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.09 (d, J = 2.01 Hz, 1H), 7.82 (d, J = 8.28 Hz, 1 H), 7.43 (d, J = 2.01 Hz, 1 H), 7.08 (d, J = 1.51 Hz, 1H), 6.71-6.86 (m, 5H), 3.83 (d, J = 5.77 Hz, 6H).
步骤3：化合物3的合成Step 3: Synthesis of compound 3
Figure PCTCN2019126178-appb-000025
Figure PCTCN2019126178-appb-000025
将3-4(80mg,265.52μmol,1eq)溶于四氢呋喃(10mL)中，冷却到0℃。在0℃下，滴加甲基溴化镁(33M,2mL,22.60eq)的2-甲基四氢呋喃溶液。反应在0℃下搅拌30分钟，再在25℃下搅拌15小时。反应结束后，加入饱和氯化铵水溶液(20mL)淬灭反应，再用乙酸乙酯(50mL)萃取。有机相用无水硫酸钠干燥，旋干，得到粗品。粗品通过薄层色谱硅胶板分离(展开剂：石油醚：乙酸乙酯＝2:5)纯化，得到化合物3。Dissolve 3-4 (80 mg, 265.52 μmol, 1 eq) in tetrahydrofuran (10 mL) and cool to 0°C. At 0°C, a solution of methyl magnesium bromide (33M, 2 mL, 22.60 eq) in 2-methyltetrahydrofuran was added dropwise. The reaction was stirred at 0°C for 30 minutes and then at 25°C for 15 hours. After the reaction was completed, saturated aqueous ammonium chloride solution (20 mL) was added to quench the reaction, and extracted with ethyl acetate (50 mL). The organic phase was dried with anhydrous sodium sulfate and spin-dried to obtain a crude product. The crude product was separated and purified by thin layer chromatography silica gel plates (developing solvent: petroleum ether: ethyl acetate = 2:5) to obtain compound 3.
LCMS:[MS+H +]＝301.9. LCMS: [MS+H + ] = 301.9.
1H NMR(400MHz,CDCl 3)δ8.12(d,J＝1.76Hz,1H),7.20(d,J＝8.03Hz,1H),7.07(d,J＝2.01Hz,1H),6.85(dd,J＝2.01,8.03Hz,1H),6.81(d,J＝2.01Hz,1H),4.31-5.07(m,4H),3.32(br s,2H),1.71(d,J＝5.27Hz,12H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.12 (d, J = 1.76 Hz, 1H), 7.20 (d, J = 8.03 Hz, 1H), 7.07 (d, J = 2.01 Hz, 1H), 6.85 (dd , J = 2.01, 8.03 Hz, 1H), 6.81 (d, J = 2.01 Hz, 1H), 4.31-5.07 (m, 4H), 3.32 (br s, 2H), 1.71 (d, J = 5.27 Hz, 12H ).
实施例4：化合物4的合成Example 4: Synthesis of Compound 4
Figure PCTCN2019126178-appb-000026
Figure PCTCN2019126178-appb-000026
化合物4的合成路线：Synthetic route of compound 4:
Figure PCTCN2019126178-appb-000027
Figure PCTCN2019126178-appb-000027
步骤1：化合物4-2的合成Step 1: Synthesis of compound 4-2
Figure PCTCN2019126178-appb-000028
Figure PCTCN2019126178-appb-000028
将3-1(3g,12.98mmol,1eq)溶于四氢呋喃(10mL)中，降低反应温度到-78℃，再慢慢滴加甲基锂(1M,64.92mL,5eq)在-78℃下搅拌1小时。TLC板监测(石油醚：乙酸乙酯＝3:1)发现反应有新点产生。反应加入水(50mL)淬灭反应，再加入乙酸乙酯(50mL*2)萃取。将有机相旋干。用快速硅胶柱纯化(石油醚/乙酸乙酯＝3:1～1:1)。得到化合物4-2。Dissolve 3-1 (3g, 12.98mmol, 1eq) in tetrahydrofuran (10mL), lower the reaction temperature to -78℃, then slowly add methyllithium (1M, 64.92mL, 5eq) and stir at -78℃ 1 hour. TLC plate monitoring (petroleum ether: ethyl acetate = 3:1) found that there were new spots in the reaction. The reaction was quenched by adding water (50 mL), and then extracted with ethyl acetate (50 mL*2). Spin the organic phase. Purified with a fast silica gel column (petroleum ether/ethyl acetate = 3:1 ~ 1:1). Compound 4-2 is obtained.
1H NMR(400MHz,CDCl 3)δ7.93(d,J＝2.0Hz,1H),7.06(d,J＝2.0Hz,1H),4.67(br s,2H),1.64(s,6H) 1H NMR (400MHz, CDCl 3 ) δ 7.93 (d, J = 2.0 Hz, 1H), 7.06 (d, J = 2.0 Hz, 1H), 4.67 (br s, 2H), 1.64 (s, 6H)
步骤2：化合物4的合成Step 2: Synthesis of compound 4
Figure PCTCN2019126178-appb-000029
Figure PCTCN2019126178-appb-000029
将4-2(500mg,2.16mmol)，六甲基二锡(1.74mmol,360mL)，二三叔丁基磷钯(330mg,645.73μmol)加入到甲苯(15mL)中，氮气保护下，80℃搅拌反应12小时。薄层色谱法检测(二氯甲烷：甲醇＝10:1)显示有大极性新点生成。反应完毕，将甲醇(10mL)和二氯甲烷(100mL)加入到反应中，待固体溶解，过滤，滤液减压浓缩。残余物先经柱层析(二氯甲烷：甲醇＝10:1)得到不纯的产物，再经高效液相制备分离(中性，色谱柱:Waters Xbridge 150*25mm 5μm；流动相:[水(10mM碳酸氢铵)-乙腈]；B(乙腈)％:10％-35％,8.2min)得到化合物4。Add 4-2 (500mg, 2.16mmol), hexamethylditin (1.74mmol, 360mL), di-tri-tert-butylphosphorus palladium (330mg, 645.73μmol) to toluene (15mL), under nitrogen protection, 80 ℃ The reaction was stirred for 12 hours. TLC detection (dichloromethane: methanol = 10:1) showed the formation of new spots with large polarity. After the reaction, methanol (10 mL) and dichloromethane (100 mL) were added to the reaction. After the solid was dissolved, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was first subjected to column chromatography (dichloromethane: methanol = 10:1) to obtain impure products, and then separated by high-performance liquid preparation (neutral, chromatographic column: Waters Xbridge 150*25mm 5μm; mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile]; B (acetonitrile)%: 10%-35%, 8.2 min) to give compound 4.
LCMS(ESI):[M+H] +＝303. LCMS (ESI): [M+H] + =303.
1H NMR(400MHz,DMSO-d 6)δ7.91(d,J＝2.0Hz,2H),7.12(d,J＝2.0Hz,2H),5.68(s,4H),5.48(br s,2H),1.52(m,12H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.91 (d, J = 2.0 Hz, 2H), 7.12 (d, J = 2.0 Hz, 2H), 5.68 (s, 4H), 5.48 (br s, 2H ), 1.52 (m, 12H).
实施例5：化合物5的合成Example 5: Synthesis of Compound 5
Figure PCTCN2019126178-appb-000030
Figure PCTCN2019126178-appb-000030
化合物5的合成路线:Synthetic route of compound 5:
Figure PCTCN2019126178-appb-000031
Figure PCTCN2019126178-appb-000031
步骤1：化合物5-3的合成Step 1: Synthesis of compound 5-3
Figure PCTCN2019126178-appb-000032
Figure PCTCN2019126178-appb-000032
将底物5-1(3g,17.74mmol,1eq)和5-2(4.03g,17.91mmol,1.01eq)溶于溶于醋酸(50mL)中，在25℃下搅拌2小时。反应结束后，反应液直接旋干。粗品用乙酸乙酯(130mL)溶解后，用饱和碳酸钠水溶液(100mL)，硫代硫酸钠(100mL，1M)和饱和食盐水(100mL)各洗涤一次。有机相用无水硫酸钠干燥，旋干，得到粗品。粗品用快速硅胶柱(石油醚：乙酸乙酯＝100:0～98:2)纯化得到5-3。Substrates 5-1 (3g, 17.74mmol, 1eq) and 5-2 (4.03g, 17.91mmol, 1.01eq) were dissolved in acetic acid (50mL) and stirred at 25°C for 2 hours. After the reaction, the reaction solution was directly spun dry. After the crude product was dissolved with ethyl acetate (130 mL), it was washed once with saturated aqueous sodium carbonate solution (100 mL), sodium thiosulfate (100 mL, 1M) and saturated brine (100 mL). The organic phase was dried with anhydrous sodium sulfate and spin-dried to obtain a crude product. The crude product was purified by flash silica gel column (petroleum ether: ethyl acetate=100:0～98:2) to obtain 5-3.
1H NMR(400MHz,CDCl 3)δ7.59-7.67(m,2H),6.22(br s,2H),3.90(s,3H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.59-7.67 (m, 2H), 6.22 (br s, 2H), 3.90 (s, 3H).
步骤2：化合物5-5的合成Step 2: Synthesis of compound 5-5
Figure PCTCN2019126178-appb-000033
Figure PCTCN2019126178-appb-000033
将化合物5-3(1g,3.39mmol,1eq)，5-4(860.66mg,3.39mmol,1eq)和醋酸钾(332.62mg,3.39mmol,1eq)溶于甲苯(15mL)中，在氮气保护下，在25℃下搅拌10分钟后，加入[1,1′-双(二苯基膦)二茂铁]二氯化钯(II)二氯甲烷[Pd(dppf)Cl 2.CH 2Cl 2](2.77g,3.39mmol,1eq)。反应升温至100℃下搅拌15小时。反应结束后，用饱和碳酸钠水溶液(60mL)淬灭，再加入乙酸乙酯(60mL)萃取。有机相用饱和食盐水(60mL)洗涤，用无水硫酸钠干燥，旋干，得到粗品。粗品用快速硅胶柱纯化(石油醚：乙酸乙酯＝100:0～98.8:1.2)。得到化合物5-5。 Compounds 5-3 (1g, 3.39mmol, 1eq), 5-4 (860.66mg, 3.39mmol, 1eq) and potassium acetate (332.62mg, 3.39mmol, 1eq) were dissolved in toluene (15mL) under nitrogen protection After stirring at 25°C for 10 minutes, [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane [Pd(dppf)Cl 2 .CH 2 Cl 2 ] (2.77g, 3.39mmol, 1eq). The reaction was heated to 100°C and stirred for 15 hours. After the reaction was completed, it was quenched with saturated sodium carbonate aqueous solution (60 mL), and ethyl acetate (60 mL) was added for extraction. The organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, and spin-dried to obtain a crude product. The crude product was purified with a flash silica gel column (petroleum ether: ethyl acetate=100:0 to 98.8:1.2). Compound 5-5 is obtained.
LCMS:[MS+H +]＝295.9。 LCMS: [MS+H + ] = 295.9.
步骤3：化合物5-6的合成Step 3: Synthesis of compounds 5-6
Figure PCTCN2019126178-appb-000034
Figure PCTCN2019126178-appb-000034
将化合物2-1(1.5g,5.45mmol,1eq)，5-5(2.09g,7.09mmol,1.3eq)，磷酸钾(3.47g,16.36mmol,3eq)和Pd(dppf)Cl 2.CH 2Cl 2(1.34g,1.64mmol,0.3eq)溶于乙二醇二甲醚(60mL)中，在80℃下搅拌15小时。反应结束后，反应液直接过滤，滤液旋干，得到粗品。粗品用快速硅胶柱(石油醚：乙酸乙酯＝100:0～60:40)纯化。得到化合物5-6。 Compound 2-1 (1.5g, 5.45mmol, 1eq) , 5-5 (2.09g, 7.09mmol, 1.3eq), potassium phosphate (3.47g, 16.36mmol, 3eq) and Pd (dppf) Cl 2 .CH 2 Cl 2 (1.34 g, 1.64 mmol, 0.3 eq) was dissolved in ethylene glycol dimethyl ether (60 mL) and stirred at 80° C. for 15 hours. After the reaction, the reaction solution was directly filtered, and the filtrate was spin-dried to obtain a crude product. The crude product was purified with a flash silica gel column (petroleum ether: ethyl acetate = 100:0 to 60:40). Compound 5-6 is obtained.
1H NMR(400MHz,CDCl 3)δ8.46(d,J＝8.78Hz,1H),8.12(br s,2H),7.88(d,J＝8.78Hz,1H),7.81(dd,J＝3.01,9.03Hz,1H),7.51(dd,J＝3.01,9.03Hz,1H),4.53(q,J＝7.03Hz,2H),3.87-3.94(m,3H),1.44(t,J＝7.15Hz,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.46 (d, J = 8.78 Hz, 1H), 8.12 (br s, 2H), 7.88 (d, J = 8.78 Hz, 1 H), 7.81 (dd, J = 3.01 , 9.03Hz, 1H), 7.51 (dd, J = 3.01, 9.03Hz, 1H), 4.53 (q, J = 7.03Hz, 2H), 3.87-3.94 (m, 3H), 1.44 (t, J = 7.15Hz , 3H).
步骤4：化合物5-7的合成Step 4: Synthesis of compounds 5-7
Figure PCTCN2019126178-appb-000035
Figure PCTCN2019126178-appb-000035
将化合物5-6(890mg,2.45mmol,1eq)溶于乙酸乙酯(100mL)中，用氮气保护后，加入Pd/C(500mg,10％纯度)，氢气球(15psi)置换三次气体，在25℃下搅拌15小时，然后在65℃下搅拌15小时。反应结束后，反应液通过硅藻土过滤。滤液直接旋干，得到化合物5-7。Compound 5-6 (890 mg, 2.45 mmol, 1 eq) was dissolved in ethyl acetate (100 mL), and after protection with nitrogen, Pd/C (500 mg, 10% purity) was added, and a hydrogen balloon (15 psi) was used to replace the gas three times. Stir at 25°C for 15 hours, then at 65°C for 15 hours. After the reaction, the reaction solution was filtered through Celite. The filtrate was directly spin-dried to obtain compound 5-7.
1H NMR(400MHz,CDCl 3)δ8.54(br s,2H),7.60-7.68(m,2H),7.45(dd,J＝3.14,9.66Hz,1H),7.16(d,J＝8.78Hz,1H),5.84(br s,2H),4.42(q,J＝7.03Hz,2H),3.90(s,3H),1.45(t,J＝7.15Hz,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.54 (br s, 2H), 7.60-7.68 (m, 2H), 7.45 (dd, J = 3.14, 9.66 Hz, 1H), 7.16 (d, J = 8.78 Hz , 1H), 5.84 (br s, 2H), 4.42 (q, J = 7.03 Hz, 2H), 3.90 (s, 3H), 1.45 (t, J = 7.15 Hz, 3H).
步骤5：化合物5-8的合成Step 5: Synthesis of compounds 5-8
Figure PCTCN2019126178-appb-000036
Figure PCTCN2019126178-appb-000036
将化合物5-7(500mg,1.50mmol,1eq)溶于四氢呋喃(50mL)中，冷却到0℃。在0℃下，滴加甲基溴化镁(3M,7.50mL,15eq)的2-甲基四氢呋喃溶液。反应在0℃下搅拌1.5小时。反应结束后，加入饱和氯化铵水溶液(100mL)淬灭反应，再用乙酸乙酯(100mL*2)萃取。有机相合并，用无水硫酸钠干燥，旋干，得到粗品。粗品通过HPLC分离(柱子型号:Boston Uni C18 40*150mm*5μm；流动相:[水(10mM碳酸氢铵溶液)-乙腈]；B(乙腈)％:28％-58％,10min)纯化，得到化合物5-8。Compound 5-7 (500 mg, 1.50 mmol, 1 eq) was dissolved in tetrahydrofuran (50 mL) and cooled to 0°C. At 0° C., a solution of methyl magnesium bromide (3M, 7.50 mL, 15 eq) in 2-methyltetrahydrofuran was added dropwise. The reaction was stirred at 0°C for 1.5 hours. After the reaction was completed, saturated aqueous ammonium chloride solution (100 mL) was added to quench the reaction, and then extracted with ethyl acetate (100 mL*2). The organic phases are combined, dried over anhydrous sodium sulfate, and spin-dried to obtain a crude product. The crude product was separated by HPLC (column model: Boston C18 40*150mm*5μm; mobile phase: [water (10mM ammonium bicarbonate solution)-acetonitrile]; B (acetonitrile)%: 28%-58%, 10min) to obtain Compound 5-8.
1H NMR(400MHz,CDCl 3)δ7.30(d,J＝8.28Hz,1H),6.99-7.10(m,2H),6.89(dd,J＝2.89,10.16Hz,1H),1.71(d,J＝1.76Hz,12H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.30 (d, J = 8.28 Hz, 1H), 6.99-7.10 (m, 2H), 6.89 (dd, J = 2.89, 10.16 Hz, 1H), 1.71 (d, J = 1.76 Hz, 12H).
步骤6：化合物5的合成Step 6: Synthesis of compound 5
Figure PCTCN2019126178-appb-000037
Figure PCTCN2019126178-appb-000037
将化合物5-8(100mg,313.11μmol,1eq)溶于乙腈(5mL)，然后通过HPLC机器分离(柱子型号:Phenomenex Gemini-NX 150*30mm*5μm；流动相:[水(0.04％氨水+10mM碳酸氢铵溶液)-乙腈]；B(乙腈)％:39％-49％,8min)纯化，得到化合物5。Compound 5-8 (100mg, 313.11μmol, 1eq) was dissolved in acetonitrile (5mL), and then separated by HPLC machine (column model: Phenomenex Gemini-NX 150*30mm*5μm; mobile phase: [water (0.04% ammonia water + 10mM Ammonium bicarbonate solution)-acetonitrile]; B (acetonitrile)%: 39%-49%, 8 min) purification to obtain compound 5.
1H NMR(400MHz,DMSO-d 6)δ7.36(d,J＝8.53Hz,1H),7.05-7.13(m,2H),6.89(s,2H),6.84(dd,J＝3.01,10.54Hz,1H),5.72(s,2H),5.55(s,1H),5.47(s,1H),1.53(d,J＝4.02Hz,12H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.36 (d, J = 8.53 Hz, 1H), 7.05-7.13 (m, 2H), 6.89 (s, 2H), 6.84 (dd, J = 3.01, 10.54 Hz, 1H), 5.72 (s, 2H), 5.55 (s, 1H), 5.47 (s, 1H), 1.53 (d, J = 4.02 Hz, 12H).
实施例6：化合物6的合成Example 6: Synthesis of Compound 6
Figure PCTCN2019126178-appb-000038
Figure PCTCN2019126178-appb-000038
化合物6的合成路线:Synthetic route of compound 6:
Figure PCTCN2019126178-appb-000039
Figure PCTCN2019126178-appb-000039
步骤1：化合物6-2的合成Step 1: Synthesis of compound 6-2
Figure PCTCN2019126178-appb-000040
Figure PCTCN2019126178-appb-000040
将化合物2-1(10g,36.36mmol,1eq)，苄醇(7.86g,72.71mmol,7.56mL,2eq)溶于乙腈(100mL)中，在20℃下加入碳酸铯(23.69g,72.71mmol,2eq)，在20℃下搅拌12小时。反应结束后，反应液用水(40mL)淬灭，再用乙酸乙酯(80mL*3)萃取。有机相合并，用无水硫酸钠干燥，过滤，旋干，得到粗品。粗品用快速硅胶柱纯化(SiO 2,石油醚/乙酸乙酯＝5:1～3:1)。得到化合物6-2。 Compound 2-1 (10g, 36.36mmol, 1eq) and benzyl alcohol (7.86g, 72.71mmol, 7.56mL, 2eq) were dissolved in acetonitrile (100mL), and cesium carbonate (23.69g, 72.71mmol, 2eq), stirred at 20°C for 12 hours. After the reaction was completed, the reaction solution was quenched with water (40 mL), and extracted with ethyl acetate (80 mL*3). The organic phases are combined, dried over anhydrous sodium sulfate, filtered and spin-dried to obtain the crude product. The crude product was purified with a fast silica gel column (SiO 2 , petroleum ether/ethyl acetate=5:1～3:1). Compound 6-2 is obtained.
1H NMR(400MHz,CDCl 3):δ8.39-8.33(m,1H),7.48-7.38(m,5H),6.99-6.93(m,1H),5.52-5.48(m,2H),4.57-4.48(m,2H),1.48-1.41(m,3H)。 1 H NMR (400 MHz, CDCl 3 ): δ 8.39-8.33 (m, 1H), 7.48-7.38 (m, 5H), 6.99-6.93 (m, 1H), 5.52-5.48 (m, 2H), 4.57- 4.48 (m, 2H), 1.48-1.41 (m, 3H).
步骤2：化合物6-3的合成Step 2: Synthesis of compound 6-3
Figure PCTCN2019126178-appb-000041
Figure PCTCN2019126178-appb-000041
将化合物6-2(4.9g,16.21mmol,1eq)溶于乙醇(90mL)中，用氮气保护后，加入钯碳(Pd/C，0.5g,16.21mmol,10％纯度,1eq)，氢气球置换三次气体，在30℃下搅拌12小时。反应结束后，反应液过滤，滤液旋干，得到粗品。粗品用快速硅胶柱纯化(SiO 2,二氯甲烷：甲醇＝10:0～10:1)。得到化合物6-3。 Compound 6-2 (4.9g, 16.21mmol, 1eq) was dissolved in ethanol (90mL), after protection with nitrogen, palladium on carbon (Pd/C, 0.5g, 16.21mmol, 10% purity, 1eq), hydrogen balloon was added The gas was replaced three times, and the mixture was stirred at 30°C for 12 hours. After the reaction, the reaction solution was filtered, and the filtrate was spin-dried to obtain a crude product. The crude product was purified with a flash silica gel column (SiO 2 , dichloromethane: methanol=10:0～10:1). Compound 6-3 is obtained.
1H NMR(400MHz,CDCl 3):δ9.17(br s,1H),7.10(d,J＝9.8Hz,1H),6.73(d,J＝9.8Hz,1H),5.41(br s,2H),4.36(q,J＝7.0Hz,2H),1.38(t,J＝7.2Hz,3H)。 1 H NMR (400 MHz, CDCl 3 ): δ 9.17 (br s, 1H), 7.10 (d, J=9.8 Hz, 1H), 6.73 (d, J=9.8 Hz, 1H), 5.41 (br s, 2H ), 4.36 (q, J = 7.0 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H).
步骤3：化合物6-5的合成Step 3: Synthesis of compound 6-5
Figure PCTCN2019126178-appb-000042
Figure PCTCN2019126178-appb-000042
将化合物6-4(1g,5.34mmol,1eq)，6-3(974.4mg,5.35mmol,1eq)溶于DMSO(20mL)，加入磷酸钾(1.70g,8.00mmol,1.5eq)，在100℃下搅拌12小时。反应结束后，加乙酸乙酯(50mL)稀释，依次用水(30mL*2)和饱和食盐水(30mL)洗涤。有机相用无水硫酸钠干燥，过滤，旋干，得到粗品。粗品用快速硅胶柱纯化(SiO 2,石油醚/乙酸乙酯＝5:1～2:1)。得到化合物6-5。 Compounds 6-4 (1g, 5.34mmol, 1eq), 6-3 (974.4mg, 5.35mmol, 1eq) were dissolved in DMSO (20mL), potassium phosphate (1.70g, 8.00mmol, 1.5eq) was added at 100°C Stir for 12 hours. After the reaction was completed, it was diluted with ethyl acetate (50 mL), and washed successively with water (30 mL*2) and saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and spin-dried to obtain the crude product. The crude product was purified with a fast silica gel column (SiO 2 , petroleum ether/ethyl acetate=5:1～2:1). Compound 6-5 is obtained.
1H NMR(400MHz,CDCl 3)δ7.64(d,J＝11.8Hz,1H),7.21-7.13(m,1H),7.02-6.97(m,1H),6.56(d,J＝6.8Hz,1H),4.44-4.31(m,2H),3.89(s,3H),1.40(t,J＝7.2Hz,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.64 (d, J = 11.8 Hz, 1H), 7.21-7.13 (m, 1H), 7.02-6.97 (m, 1H), 6.56 (d, J = 6.8 Hz, 1H), 4.44-4.31 (m, 2H), 3.89 (s, 3H), 1.40 (t, J = 7.2 Hz, 3H).
步骤4：化合物6的合成Step 4: Synthesis of compound 6
Figure PCTCN2019126178-appb-000043
Figure PCTCN2019126178-appb-000043
将化合物6-5(200mg,572.55μmol,1eq)溶于四氢呋喃(40mL)中，冷却到0℃。在0℃下，滴加甲基溴化镁(3M,5mL,26.20eq)的2-甲基四氢呋喃溶液。反应在0℃下搅拌1小时，再在15℃下搅拌15小时。反应结束后，加入饱和氯化铵水溶液(50mL)淬灭反应，再用乙酸乙酯(60mL)萃取。有机相用无水硫酸钠干燥，旋干，得到粗品。粗品通过HPLC分离(柱子型号:Waters Xbridge 150*25mm 5μm；流动相:[水(10mM碳酸氢铵溶液)-乙腈]；B(乙腈)％:15％-45％,10min)纯化，得到化合物6。Compound 6-5 (200 mg, 572.55 μmol, 1 eq) was dissolved in tetrahydrofuran (40 mL) and cooled to 0°C. At 0°C, a solution of methyl magnesium bromide (3M, 5 mL, 26.20 eq) in 2-methyltetrahydrofuran was added dropwise. The reaction was stirred at 0°C for 1 hour and then at 15°C for 15 hours. After the reaction was completed, saturated aqueous ammonium chloride solution (50 mL) was added to quench the reaction, and extracted with ethyl acetate (60 mL). The organic phase was dried with anhydrous sodium sulfate and spin-dried to obtain a crude product. The crude product was separated by HPLC (column model: Waters Xbridge 150*25mm 5μm; mobile phase: [water (10mM ammonium bicarbonate solution)-acetonitrile]; B (acetonitrile)%: 15%-45%, 10min) to obtain compound 6 .
LCMS:[MS+H+]＝336.0。LCMS: [MS+H+] = 336.0.
1H NMR(400MHz,DMSO-d 6)δ7.06(d,J＝8.28Hz,1H),6.88(d,J＝13.05Hz,1H),6.55(d,J＝8.28Hz,1H),6.33(d,J＝7.53Hz,1H),5.37(s,1H),5.30(br d,J＝3.01Hz,4H),5.26(s,1H),1.48(s,6H),1.38(s,6H)。 1H NMR (400MHz, DMSO-d 6) δ7.06 (d, J = 8.28Hz, 1H), 6.88 (d, J = 13.05Hz, 1H), 6.55 (d, J = 8.28Hz, 1H), 6.33 ( d, J = 7.53 Hz, 1H), 5.37 (s, 1H), 5.30 (br d, J = 3.01 Hz, 4H), 5.26 (s, 1H), 1.48 (s, 6H), 1.38 (s, 6H) .
实施例7：化合物7的合成Example 7: Synthesis of Compound 7
Figure PCTCN2019126178-appb-000044
Figure PCTCN2019126178-appb-000044
化合物7的合成路线：Synthetic route of compound 7:
Figure PCTCN2019126178-appb-000045
Figure PCTCN2019126178-appb-000045
步骤1：化合物7-2的合成Step 1: Synthesis of compound 7-2
Figure PCTCN2019126178-appb-000046
Figure PCTCN2019126178-appb-000046
向化合物7-1(2g,7.19mmol,1eq)的甲苯(30mL)溶液中加入5-4(3.65g,14.39mmol,2eq)，Pd(dppf)Cl 2(526.35mg,719.34μmol,0.1eq)，醋酸钾(1.41g,14.39mmol,2eq)，在110℃反应3小时。待反应结束后将反应液减压浓缩得到粗品7-2。 (30mL) was added 5-4 (3.65g, 14.39mmol, 2eq) in toluene solution of compound 7-1 (2g, 7.19mmol, 1eq) a, Pd (dppf) Cl 2 ( 526.35mg, 719.34μmol, 0.1eq) , Potassium acetate (1.41g, 14.39mmol, 2eq), reacted at 110 ℃ for 3 hours. After the reaction is completed, the reaction solution is concentrated under reduced pressure to obtain crude product 7-2.
步骤2：化合物7-3的合成Step 2: Synthesis of compound 7-3
Figure PCTCN2019126178-appb-000047
Figure PCTCN2019126178-appb-000047
向化合物7-2(1.63g,7.07mmol,1eq)的甲苯(50mL)和水(10mL)溶液中加入化合物3-1(2.3g,7.07mmol,1eq)，碳酸铯(4.61g,14.14mmol,2eq)，Pd(dppf)Cl 2(517.32mg,707.00μmol,0.1eq)，在110℃，氮气环境下反应6小时。待反应结束后将反应液用硅藻土过滤，滤液减压浓缩得到粗品。粗品用硅胶柱层析法分离(SiO 2，石油醚/乙酸乙酯＝5:1～0:1)。得到化合物7-3。 To a solution of compound 7-2 (1.63 g, 7.07 mmol, 1 eq) in toluene (50 mL) and water (10 mL) was added compound 3-1 (2.3 g, 7.07 mmol, 1 eq), cesium carbonate (4.61 g, 14.14 mmol, 2eq), Pd(dppf)Cl 2 (517.32mg, 707.00μmol, 0.1eq), reacted at 110°C under a nitrogen atmosphere for 6 hours. After the reaction was completed, the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (SiO 2 , petroleum ether/ethyl acetate=5:1～0:1). Compound 7-3 is obtained.
LCMS:350.1[M+1] +. LCMS:350.1[M+1] + .
步骤3：化合物7-4的合成Step 3: Synthesis of compound 7-4
Figure PCTCN2019126178-appb-000048
Figure PCTCN2019126178-appb-000048
向化合物7-3(1.58g,4.52mmol,1eq)的甲醇(50mL)和乙酸乙酯(50mL)溶液中加入Pd/C(1.7g,5％纯 度)，在氢气环境下15psi，20℃反应3小时。待反应结束后将反应液用硅藻土过滤，滤液减压浓缩，得到化合物7-4。To a solution of compound 7-3 (1.58 g, 4.52 mmol, 1 eq) in methanol (50 mL) and ethyl acetate (50 mL) was added Pd/C (1.7 g, 5% purity), and the reaction was carried out at 15 psi under hydrogen atmosphere at 20°C. 3 hours. After the reaction was completed, the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain compound 7-4.
LCMS:320[M+1] +. LCMS:320[M+1] + .
1H NMR(400MHz,DMSO-d 6)δppm 7.96(t,J＝1.76Hz,1H),7.54(d,J＝11.84Hz,1H),7.39(s,1H),6.95(d,J＝6.58Hz,1H),6.82(s,2H),6.66(s,2H),3.83(d,J＝3.96Hz,6H). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.96 (t, J = 1.76 Hz, 1H), 7.54 (d, J = 11.84 Hz, 1 H), 7.39 (s, 1 H), 6.95 (d, J = 6.58 Hz, 1H), 6.82 (s, 2H), 6.66 (s, 2H), 3.83 (d, J = 3.96Hz, 6H).
步骤4：化合物7的合成Step 4: Synthesis of compound 7
Figure PCTCN2019126178-appb-000049
Figure PCTCN2019126178-appb-000049
在0℃，向化合物7-4(1.5g,4.70mmol,1eq)的四氢呋喃(150mL)溶液中加入甲基溴化镁(3M,31.32mL,20eq)，在20℃反应3小时。待反应结束后将反应液倒入饱和氯化铵溶液中，加入50mL乙酸乙酯分液，水相用乙酸乙酯萃取(50mL*3)，合并有机相，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品用HPLC分离(柱子型号:Xtimate C18 150*25mm*5μm；流动相:[水(10mM碳酸氢铵溶液)-乙腈]；B(乙腈)％:25％-45％,10.5min)分离。得到化合物7。To a solution of compound 7-4 (1.5 g, 4.70 mmol, 1 eq) in tetrahydrofuran (150 mL) was added methylmagnesium bromide (3M, 31.32 mL, 20 eq) at 0°C, and the reaction was carried out at 20°C for 3 hours. After the reaction is completed, the reaction solution is poured into a saturated ammonium chloride solution, 50 mL of ethyl acetate is added for liquid separation, the aqueous phase is extracted with ethyl acetate (50 mL*3), the organic phases are combined, dried over anhydrous sodium sulfate, filtered, and reduced Concentrate by pressure to obtain crude product. The crude product was separated by HPLC (column model: Xtimate C18 150*25mm*5μm; mobile phase: [water (10mM ammonium bicarbonate solution)-acetonitrile]; B (acetonitrile)%: 25%-45%, 10.5min). Compound 7 is obtained.
LCMS:320.0[M+1] +； LCMS: 320.0[M+1] + ;
1H NMR(400MHz,DMSO-d 6)δppm 7.77(s,1H),7.05(s,1H),6.91(d,J＝12.28Hz,1H),6.67(d,J＝7.46Hz,1H),5.63(s,2H),5.27-5.48(m,4H),1.51(s,12H) 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.77 (s, 1H), 7.05 (s, 1H), 6.91 (d, J = 12.28 Hz, 1H), 6.67 (d, J = 7.46 Hz, 1H), 5.63(s, 2H), 5.27-5.48(m, 4H), 1.51(s, 12H)
实施例8：化合物8的合成Example 8: Synthesis of Compound 8
Figure PCTCN2019126178-appb-000050
Figure PCTCN2019126178-appb-000050
化合物8的合成路线：Synthetic route of compound 8:
Figure PCTCN2019126178-appb-000051
Figure PCTCN2019126178-appb-000051
步骤1：化合物8-1的合成Step 1: Synthesis of compound 8-1
Figure PCTCN2019126178-appb-000052
Figure PCTCN2019126178-appb-000052
将化合物3-4(1g,3.32mmol,1eq)和NCS(509.67mg,3.82mmol,1.15eq)溶于冰醋酸(60mL)，在25℃下搅拌15小时。反应结束后，反应液通过饱和碳酸钠水溶液(200mL)调节PH～9，再加入乙酸乙酯(150mL)萃取。有机相在用饱和食盐水(50mL)洗涤一次，然后用无水硫酸钠干燥，旋干，得到粗品。粗品用快速硅胶柱(石油醚：乙酸乙酯＝100:0～70:30)纯化。得到化合物8-1。Compound 3-4 (1 g, 3.32 mmol, 1 eq) and NCS (509.67 mg, 3.82 mmol, 1.15 eq) were dissolved in glacial acetic acid (60 mL) and stirred at 25° C. for 15 hours. After the reaction was completed, the reaction solution was adjusted to pH-9 by saturated sodium carbonate aqueous solution (200 mL), and then extracted with ethyl acetate (150 mL). The organic phase was washed once with saturated brine (50 mL), then dried over anhydrous sodium sulfate, and spin-dried to obtain a crude product. The crude product was purified with a flash silica gel column (petroleum ether: ethyl acetate = 100:0 ~ 70:30). Compound 8-1 is obtained.
1H NMR(400MHz,CDCl 3)δ8.10(d,J＝1.76Hz,1H),7.97(s,1H),7.12(d,J＝1.76Hz,1H),6.63(s,1H),5.83(br s,4H),4.01(s,3H),3.91(s,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.10 (d, J=1.76 Hz, 1H), 7.97 (s, 1H), 7.12 (d, J=1.76 Hz, 1H), 6.63 (s, 1H), 5.83 (br s, 4H), 4.01 (s, 3H), 3.91 (s, 3H).
步骤2：化合物8的合成Step 2: Synthesis of compound 8
Figure PCTCN2019126178-appb-000053
Figure PCTCN2019126178-appb-000053
将化合物8-1(265mg,789.30μmol,1eq)溶于四氢呋喃(50mL)中，冷却到0℃。在0℃下，滴加甲基溴化镁(3M,4mL,15.20eq)的2-甲基四氢呋喃溶液。反应在0℃下搅拌2小时，再在25℃下搅拌15小时。反应结束后，加入饱和氯化铵水溶液(50mL)淬灭反应，再用乙酸乙酯(60mL*2)萃取。有机相合并，用无水硫酸钠干燥，旋干，得到粗品。粗品通过HPLC分离(柱子型号:Waters Xbridge 150*25mm*5μm；流动相:[水(10mM碳酸氢铵溶液)-乙腈]；B(乙腈)％:25％-48％,7.8min)纯化，得到化合物8。Compound 8-1 (265 mg, 789.30 μmol, 1 eq) was dissolved in tetrahydrofuran (50 mL) and cooled to 0°C. At 0° C., a solution of methyl magnesium bromide (3M, 4 mL, 15.20 eq) in 2-methyltetrahydrofuran was added dropwise. The reaction was stirred at 0°C for 2 hours and then at 25°C for 15 hours. After the reaction was completed, saturated aqueous ammonium chloride solution (50 mL) was added to quench the reaction, and extracted with ethyl acetate (60 mL*2). The organic phases are combined, dried over anhydrous sodium sulfate, and spin-dried to obtain a crude product. The crude product was separated by HPLC (column model: Waters Xbridge 150*25mm*5μm; mobile phase: [water (10mM ammonium bicarbonate solution)-acetonitrile]; B (acetonitrile)%: 25%-48%, 7.8min) to obtain Compound 8.
LCMS:[MS+H+]＝336.0；LCMS: [MS+H+]=336.0;
1H NMR(400MHz,DMSO-d 6)δ7.66(d,J＝2.01Hz,1H),7.07(s,1H),6.96(d,J＝2.01Hz,1H),6.61(s,1H),5.61(br d,J＝17.32Hz,4H),5.47(s,1H),5.34(s,1H),1.51(s,12H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.66 (d, J = 2.01 Hz, 1H), 7.07 (s, 1H), 6.96 (d, J = 2.01 Hz, 1H), 6.61 (s, 1H) , 5.61 (br d, J = 17.32 Hz, 4H), 5.47 (s, 1H), 5.34 (s, 1H), 1.51 (s, 12H).
实施例9：化合物9的合成Example 9: Synthesis of Compound 9
Figure PCTCN2019126178-appb-000054
Figure PCTCN2019126178-appb-000054
化合物9的合成路线：Synthetic route of compound 9:
Figure PCTCN2019126178-appb-000055
Figure PCTCN2019126178-appb-000055
步骤1：化合物9-2的合成Step 1: Synthesis of compound 9-2
Figure PCTCN2019126178-appb-000056
Figure PCTCN2019126178-appb-000056
将化合物9-1(24.8g,120.37mmol,1eq)，苄胺(15.48g,144.45mmol,15.75mL,1.2eq)溶于DMF(200mL)中，在20℃下加入三乙胺(36.54g,361.12mmol,50.26mL,3eq)。反应液在20℃下搅拌21小时。待反应完全加入水(250mL)淬灭反应，再加入乙酸乙酯(500mL*2)萃取。将有机相旋干。用快速硅胶柱纯化(SiO 2，石油醚/乙酸乙酯＝5:1～3:1)。得到化合物9-2。 Compound 9-1 (24.8g, 120.37mmol, 1eq) and benzylamine (15.48g, 144.45mmol, 15.75mL, 1.2eq) were dissolved in DMF (200mL), and triethylamine (36.54g, 361.12mmol, 50.26mL, 3eq). The reaction solution was stirred at 20°C for 21 hours. After the reaction was completed, water (250 mL) was added to quench the reaction, and then ethyl acetate (500 mL*2) was added for extraction. Spin the organic phase. Purified with a fast silica gel column (SiO 2 , petroleum ether/ethyl acetate=5:1～3:1). Compound 9-2 is obtained.
LCMS(ESI):[M+H] +:277.1. LCMS (ESI): [M+H] + : 277.1.
1H NMR(400MHz,CDCl 3)δ8.71(s,1H),8.55(br s,1H),7.36-7.43(m,2H),7.29-7.35(m,3H),6.56(s,1H),4.44(d,J＝5.52Hz,2H),3.88-3.92(m,3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.71 (s, 1H), 8.55 (br s, 1H), 7.36-7.43 (m, 2H), 7.29-7.35 (m, 3H), 6.56 (s, 1H) , 4.44 (d, J = 5.52 Hz, 2H), 3.88-3.92 (m, 3H).
步骤2：化合物9-3的合成Step 2: Synthesis of compound 9-3
Figure PCTCN2019126178-appb-000057
Figure PCTCN2019126178-appb-000057
将化合物9-2(5g,18.07mmol,1eq)，甲醇钠(9.76g,180.69mmol,10eq)溶于MeOH(50mL)中，氮气保护下，90℃搅拌反应15小时。待反应结束后用快速硅胶柱纯化(SiO 2，石油醚/乙酸乙酯＝5:1～3:1)。得到化合物9-3。 Compound 9-2 (5 g, 18.07 mmol, 1 eq), sodium methoxide (9.76 g, 180.69 mmol, 10 eq) were dissolved in MeOH (50 mL), and the reaction was stirred at 90° C. for 15 hours under nitrogen protection. After the reaction is completed, it is purified with a fast silica gel column (SiO 2 , petroleum ether/ethyl acetate=5:1～3:1). Compound 9-3 is obtained.
LCMS(ESI):[M+H]+:273.LCMS(ESI):[M+H]+:273.
步骤3：化合物9-4的合成Step 3: Synthesis of compound 9-4
Figure PCTCN2019126178-appb-000058
Figure PCTCN2019126178-appb-000058
将化合物9-3(3.26g,11.97mmol,1eq)，三甲基氯硅烷(5.20g,47.89mmol,6.08mL,4eq)，NaI(7.18g,47.89mmol,4eq)溶于乙腈(50mL)中，氮气保护下，80℃搅拌反应15小时。待反应结束后，将溶液用碳酸氢钠调节溶液PH＝7。再用水(20mL)淬灭，然后用二氯甲烷(100mL)萃取两次，最后将有机相结合，用旋转蒸发仪旋干，粗品用快速硅胶柱纯化(SiO 2，石油醚/乙酸乙酯＝5/1～3:1)得到化合物9-4。 Compound 9-3 (3.26g, 11.97mmol, 1eq), trimethylchlorosilane (5.20g, 47.89mmol, 6.08mL, 4eq), NaI (7.18g, 47.89mmol, 4eq) was dissolved in acetonitrile (50mL) Under nitrogen, the reaction was stirred at 80°C for 15 hours. After the reaction was completed, the solution was adjusted to pH=7 with sodium bicarbonate. It was quenched with water (20 mL), and then extracted twice with dichloromethane (100 mL). Finally, the organic phases were combined and dried on a rotary evaporator. The crude product was purified by flash silica gel column (SiO 2 , petroleum ether/ethyl acetate= 5/1 to 3:1) Compound 9-4 is obtained.
LCMS(ESI):[M+H] +:259.1 LCMS(ESI): [M+H] + : 259.1
1H NMR(400MHz,CDCl 3)δ7.47(br s,1H),6.47-6.58(m,5H),4.65(s,1H),3.55(br d,J＝5.27Hz,2H),3.00-3.08(m,3H) 1 H NMR (400 MHz, CDCl 3 ) δ 7.47 (br s, 1H), 6.47-6.58 (m, 5H), 4.65 (s, 1H), 3.55 (br d, J = 5.27 Hz, 2H), 3.00- 3.08(m,3H)
步骤4：化合物9-6的合成Step 4: Synthesis of compound 9-6
Figure PCTCN2019126178-appb-000059
Figure PCTCN2019126178-appb-000059
将化合物9-4(2.29g,8.87mmol,1eq)，化合物9-5(2.77g,10.64mmol,1.2eq)，碘化亚铜(337.73mg,1.77 mmol,0.2eq)，碳酸钾(2.45g,17.73mmol,2eq)和(1S，2S)-N1，N2-二甲基环己烷-1,2-二胺(252.24mg,1.77mmol,0.2eq)溶于甲苯(30mL)中，氮气保护下，110℃搅拌反应13小时。反应结束后将溶液过滤后用旋转蒸发仪旋干。用快速硅胶柱纯化(SiO 2，石油醚/乙酸乙酯＝1:1～0:1)得到化合物9-6。 Compound 9-4 (2.29g, 8.87mmol, 1eq), compound 9-5 (2.77g, 10.64mmol, 1.2eq), cuprous iodide (337.73mg, 1.77mmol, 0.2eq), potassium carbonate (2.45g , 17.73mmol, 2eq) and (1S, 2S)-N1,N2-dimethylcyclohexane-1,2-diamine (252.24mg, 1.77mmol, 0.2eq) dissolved in toluene (30mL), nitrogen protection The reaction was stirred at 110°C for 13 hours. After the reaction was completed, the solution was filtered and dried with a rotary evaporator. Purification with a flash silica gel column (SiO 2 , petroleum ether/ethyl acetate = 1:1 to 0:1) gave compound 9-6.
LCMS(ESI):[M+H] +:438.1。 LCMS (ESI): [M+H] + : 438.1.
步骤5：化合物9-7的合成Step 5: Synthesis of compound 9-7
Figure PCTCN2019126178-appb-000060
Figure PCTCN2019126178-appb-000060
将化合物9-6(1g,2.29mmol,1eq)溶于四氢呋喃(30mL)中，在氮气氛围下向混合溶液中加入钯碳(1.5g,纯度10％)。氢气氛围下，65℃搅拌12小时。反应结束后将反应混合物过滤后旋干。用快速硅胶柱纯化(SiO 2，石油醚/乙酸乙酯＝1:1～0:1)得到化合物9-7。 Compound 9-6 (1 g, 2.29 mmol, 1 eq) was dissolved in tetrahydrofuran (30 mL), and palladium carbon (1.5 g, purity 10%) was added to the mixed solution under a nitrogen atmosphere. Under a hydrogen atmosphere, the mixture was stirred at 65°C for 12 hours. After the reaction, the reaction mixture was filtered and spin-dried. Purification with a flash silica gel column (SiO 2 , petroleum ether/ethyl acetate = 1:1 to 0:1) gave compound 9-7.
LCMS(ESI):[M+H] +:318.1 LCMS(ESI): [M+H] + : 318.1
1H NMR: 1H NMR(400MHz,DMSO-d 6)δ8.12(s,1H),7.76(d,J＝8.53Hz,1H),7.06(br s,2H),6.84(s,2H),6.77(d,J＝1.76Hz,1H),6.51(dd,J＝2.01,8.53Hz,1H),5.42(s,1H),3.81(s,3H),3.74(s,3H) 1H NMR: 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.12 (s, 1H), 7.76 (d, J = 8.53 Hz, 1H), 7.06 (br s, 2H), 6.84 (s, 2H), 6.77 (d, J = 1.76 Hz, 1H), 6.51 (dd, J = 2.01, 8.53 Hz, 1H), 5.42 (s, 1H), 3.81 (s, 3H), 3.74 (s, 3H)
步骤6：化合物9的合成Step 6: Synthesis of compound 9
Figure PCTCN2019126178-appb-000061
Figure PCTCN2019126178-appb-000061
将化合物9-7(200mg,630.33μmol,1eq)溶于四氢呋喃(20mL)中，氮气氛围下，将反应液在干冰乙醇浴中降温到-78℃并向其中缓慢的滴加甲基锂(1.6M,5.91mL,15eq)。滴加完成后将反应液缓慢的升温至0℃搅拌30分钟。反应结束后在0℃下将反应液用水(10mL)淬灭，用水(5mL)稀释后用THF(40mL)萃取。有机相结合后用无水硫酸钠干燥，过滤，旋干得到化合物9。Compound 9-7 (200 mg, 630.33 μmol, 1 eq) was dissolved in tetrahydrofuran (20 mL). Under a nitrogen atmosphere, the reaction solution was cooled to -78°C in a dry ice ethanol bath, and methyl lithium (1.6 M, 5.91 mL, 15 eq). After the dropwise addition was completed, the reaction solution was slowly raised to 0°C and stirred for 30 minutes. After the reaction was completed, the reaction solution was quenched with water (10 mL) at 0°C, diluted with water (5 mL), and extracted with THF (40 mL). After the organic phases are combined, they are dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain compound 9.
LCMS(ESI):[M+H] +:318. LCMS (ESI): [M+H] + :318.
1H NMR(400MHz,DMSO-d 6)δ6.20(d,J＝8.28Hz,1H),6.14(s,1H),5.69(d,J＝2.26Hz,1H),5.53(dd,J＝2.13, 8.16Hz,1H),5.45(s,2H),4.73(s,2H),4.57(s,1H),4.53(s,1H),4.41(s,1H),0.67(s,6H),0.60(s,6H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 6.20 (d, J=8.28 Hz, 1H), 6.14 (s, 1H), 5.69 (d, J=2.26 Hz, 1H), 5.53 (dd, J= 2.13, 8.16Hz, 1H), 5.45(s, 2H), 4.73(s, 2H), 4.57(s, 1H), 4.53(s, 1H), 4.41(s, 1H), 0.67(s, 6H), 0.60(s,6H).
实验例1：体外醛捕捉能力实验Experimental Example 1: In vitro aldehyde capture ability experiment
1.实验目的及过程1. Experimental purpose and process
目的：干眼症产生是由眼睛内部出现炎症，这些炎症会在体内产生一些醛，这些醛如果不及时排除出去，会加速炎症的症状，使干眼症发生恶化。本实验通过模拟体内环境，根据药物和体内醛的络合能力，选取相对较优的化合物。Purpose: Dry eye syndrome is caused by inflammation inside the eye. These inflammations will produce some aldehydes in the body. If these aldehydes are not eliminated in time, they will accelerate the symptoms of inflammation and make dry eye syndrome worse. In this experiment, by simulating the in vivo environment, according to the complexing ability of the drug and the aldehyde in the body, a relatively superior compound is selected.
过程：将磺丁基-B-环糊精(310毫克)溶解于磷酸缓冲液(1.25毫升)配好溶液。Procedure: Dissolve sulfobutyl-B-cyclodextrin (310 mg) in phosphate buffer (1.25 mL) to prepare a solution.
室温下，往反应瓶中加入壬醛(5.0毫克，32微摩尔，1.0当量)和三油酸甘油酯(300毫克)，加入上述配好的溶液后，再加入亚油酸(300毫克)，最后加入包含本发明化合物(32微摩尔，1.0当量)的二甲基亚砜(0.15毫升)溶液，反应液于20-23℃反应。At room temperature, add nonanal (5.0 mg, 32 micromolar, 1.0 equivalent) and triolein (300 mg) to the reaction flask. After adding the above prepared solution, add linoleic acid (300 mg). Finally, a solution of the compound of the present invention (32 micromolar, 1.0 equivalent) in dimethyl sulfoxide (0.15 ml) was added, and the reaction solution was reacted at 20-23°C.
分别在搅拌反应10分钟，100分钟，200分钟，300分钟时，静置2分钟分层后取样进行高效液相检测。When the reaction was stirred for 10 minutes, 100 minutes, 200 minutes, and 300 minutes, the samples were separated after standing for 2 minutes for high-performance liquid detection.
取样方式：移液枪取样上层乳化层25微升，下层水相50微升，加甲醇1毫升稀释。Sampling method: Pipette gun to sample 25 microliters of the upper emulsified layer, 50 microliters of the lower aqueous phase, and dilute with 1 ml of methanol.
2.实验结果2. Experimental results
壬醛在波长254nm下紫外吸收较弱，对络合产物的含量整体影响较小，因此取高效液相254nm下络合物的百分含量做比较，来观察化合物的醛的捕获络合醛的能力。见图1和表1：Nonanal has a weak UV absorption at a wavelength of 254 nm and has a small overall effect on the content of the complexed product. Therefore, the percentage of the complex at a high-performance liquid phase at 254 nm is compared to observe the aldehyde capture of the compound. ability. See Figure 1 and Table 1:
Figure PCTCN2019126178-appb-000062
Figure PCTCN2019126178-appb-000062
表1 化合物醛捕捉能力测试结果统计Table 1 Statistics of test results of compound aldehyde capture ability
化合物Chemical compound 线性方程Linear equation 斜率Slope 回归系数R 2 Regression coefficient R 2 曲线下面积AUC(min.转化率)Area under the curve AUC (min. conversion rate)
化合物1Compound 1 y＝0.0157x+1.718y=0.0157x+1.718 0.01570.0157 R 2＝0.7521 R 2 =0.7521 12571257
化合物2Compound 2 y＝0.0103x+2.7459y=0.0103x+2.7459 0.01030.0103 R 2＝0.9712 R 2 = 0.9712 12711271
化合物3Compound 3 y＝0.0652x+3.362y=0.0652x+3.362 0.06520.0652 R 2＝0.9891 R 2 = 0.9891 39793979
化合物4Compound 4 y＝0.0589x+1.3064y=0.0589x+1.3064 0.05890.0589 R 2＝0.9964 R 2 =0.9964 30613061
化合物5Compound 5 y＝0.0271x+0.1945y=0.0271x+0.1945 0.02710.0271 R 2＝0.9326 R 2 = 0.9326 12081208
化合物6Compound 6 y＝0.1083x+12.77y=0.1083x+12.77 0.10830.1083 R 2＝0.9027 R 2 = 0.9027 89538953
化合物7Compound 7 y＝0.1002x+7.7455y=0.1002x+7.7455 0.10020.1002 R 2＝0.9686 R 2 = 0.9686 69446944
化合物8Compound 8 y＝0.0519x+4.9828y=0.0519x+4.9828 0.05190.0519 R 2＝0.9535 R 2 = 0.9535 38793879
化合物9Compound 9 y＝0.1241x+14.964y=0.1241x+14.964 0.12410.1241 R 2＝0.9299 R 2 = 0.9299 1028410284
HPLC分析方法为XBRIGE 2.5μm,3.0*100mm 5-95CD_XBEH_12min_0.8.lcm或XBRIGE2.5μm,3.0*100mm 5-80CD_XBEH_12min_0.8.lcmHPLC analysis method is XBRIGE 2.5μm, 3.0*100mm 5-95CD_XBEH_12min_0.8.lcm or XBRIGE 2.5μm, 3.0*100mm 5-80CD_XBEH_12min_0.8.lcm
具体条件：XBRIGE 2.5μm,3.0*100mm 5-80CD_XBEH_12min_0.8.lcmSpecific conditions: XBRIGE 2.5μm, 3.0*100mm 5-80CD_XBEH_12min_0.8.lcm
Figure PCTCN2019126178-appb-000063
Figure PCTCN2019126178-appb-000063
XBRIGE 2.5μm,3.0*100mm 5-95CD_XBEH_12min_0.8.lcmXBRIGE 2.5μm, 3.0*100mm 5-95CD_XBEH_12min_0.8.lcm
Figure PCTCN2019126178-appb-000064
Figure PCTCN2019126178-appb-000064
以化合物7为例，其反应300分钟后，检测HPLC分析方法为XBRIGE 2.5μm,3.0*100mm 5-80CD_XBEH_12min_0.8.lcm，Taking compound 7 as an example, after 300 minutes of reaction, the detection HPLC analysis method is XBRIGE 2.5μm, 3.0*100mm 5-80CD_XBEH_12min_0.8.lcm,
保留时间6.689分钟；6.787分钟；6.966分钟；7.102分钟为络合一分子醛的产物的吸收峰；Retention time 6.689 minutes; 6.787 minutes; 6.966 minutes; 7.102 minutes is the absorption peak of the product of complexing a molecule of aldehyde;
保留时间8.905分钟；9.010分钟；9.075分钟为络合双分子醛的产物的吸收峰。The retention time is 8.905 minutes; 9.010 minutes; 9.075 minutes is the absorption peak of the bimolecular aldehyde complexed product.
具体络合产物254nm百分含量计算为上述保留时间吸收峰百分含量之和，即(1.839+1.715+14.993+13.029)％+(1.004+2.212+1.247)％＝36.039％The specific complex product 254nm percent content is calculated as the sum of the retention time absorption peak percent content, ie (1.839+1.715+14.993+13.029)%+(1.004+2.212+1.247)%=36.039%
本发明化合物络合产物百分含量具体HPLC数据如下表2：The specific HPLC data of the percentage content of the complex product of the compound of the present invention are as follows in Table 2:
Figure PCTCN2019126178-appb-000065
Figure PCTCN2019126178-appb-000065
结论：实验显示本发明化合物具有非常显著的络合醛的能力和速度。Conclusion: The experiments show that the compounds of the present invention have a very significant ability and speed to complex aldehydes.
实验例2：体外评价Experimental Example 2: In vitro evaluation
试验目的：研究化合物对人肝微粒体细胞色素P450抑制作用Test purpose: To study the inhibitory effect of compounds on human liver microsome cytochrome P450
试验过程：化合物对人肝微粒体细胞色素P450(CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4)的抑制性的研究，选用了混合人肝微粒体作为CYP450酶源，将不同浓度的化合物(10,5,1.5，0.5,0.15,0.05,0.015mM)与5个CYP酶的探针底物(其中CYP3A4采用两个底物)和辅助因子(NADPH)一起孵育，测定化合物对每个CYP酶抑制的IC 50值。试验结果如下： Test process: The compound's inhibitory study on human liver microsomal cytochrome P450 (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4), mixed human liver microsomes were selected as the source of CYP450 enzyme, and different concentrations of compounds (10,5 , 1.5, 0.5, 0.15, 0.05, 0.015 mM) were incubated with 5 probe substrates of CYP enzymes (including two substrates for CYP3A4) and cofactors (NADPH) to determine the compound’s IC for each CYP enzyme inhibition 50 value. The test results are as follows:
表3 本发明化合物对人肝微粒体细胞色素P450同工酶抑制作用试验结果Table 3 Test results of the compounds of the present invention on human liver microsomal cytochrome P450 isoenzyme inhibition
化合物编号Compound number CYP1A2/CYP2C9/CYP2C19/CYP2D6/CYP3A4(μM)CYP1A2/CYP2C9/CYP2C19/CYP2D6/CYP3A4(μM)
化合物3Compound 3 >50/>50/>50/>50/>50>50/>50/>50/>50/>50
化合物7Compound 7 >50/>50/>50/>50/>50>50/>50/>50/>50/>50
化合物8 Compound 8 >50/>50/>50/>50/>50>50/>50/>50/>50/>50
结论：本发明安全性高，发生药物相互作用的可能性低。Conclusion: The invention has high safety and low possibility of drug interaction.
实验例3：化合物药代动力学评价Experimental Example 3: Compound pharmacokinetic evaluation
一、One,
实验目的：测试化合物在SD大鼠体内5天毒理研究The purpose of the experiment: Toxic study of test compounds in SD rats for 5 days
实验材料：SD大鼠(雄性，200-300g，7～9周龄，上海灵畅)Experimental material: SD rat (male, 200-300g, 7-9 weeks old, Shanghai Lingchang)
实验操作：Experimental operation:
以标准方案测试化合物静脉注射啮齿类动物药代特征，实验中候选化合物配成澄清溶液，给予SD大鼠20mg/kg，连续5天单次静脉注射给药。静注溶媒为10％羟丙基β环糊***溶液。在给药第一天和第五天给药后0.033、0.083、0.25、0.5、1、2、4、8、24小时收集全血样品，3000r离心10分钟，分离上清得血浆样品，将15μL血浆样品和300μL含有内标的乙腈溶液沉淀蛋白混合，离心取上清液2μL进样，以LC-MS/MS分析方法定量分析血药浓度，并计算药代参数，如清除率，半衰期，药时曲线下面积。The pharmacokinetic characteristics of rodents were intravenously tested using standard protocols. In the experiment, the candidate compounds were formulated as clear solutions, and SD rats were given 20 mg/kg, which was given as a single intravenous injection for 5 consecutive days. The intravenous injection solvent is 10% hydroxypropyl β cyclodextrin aqueous solution. Collect the whole blood samples at 0.033, 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after the first and fifth days of dosing, centrifuge at 3000r for 10 minutes, and separate the supernatant to obtain a plasma sample. Plasma samples were mixed with 300 μL of acetonitrile solution containing internal standard precipitated protein, centrifuged to take 2 μL of supernatant for injection, quantitative analysis of blood drug concentration by LC-MS/MS analysis method, and calculation of pharmacokinetic parameters, such as clearance rate, half-life, drug time Area under the curve.
实验结果：Experimental results:
表4 药代动力学测试结果Table 4 Pharmacokinetic test results
Figure PCTCN2019126178-appb-000066
Figure PCTCN2019126178-appb-000066
结论：本发明化合物连续5天注射给药没有药物蓄积风险。Conclusion: The compound of the present invention is administered by injection for 5 consecutive days without risk of drug accumulation.
二、two,
实验目的：测试化合物在比格犬体内药代动力学研究Experimental purpose: Pharmacokinetic study of test compounds in Beagle dogs
实验材料：比格犬(雄性,8-11kg,大于等于6个月，玛斯)Experimental material: Beagle (male, 8-11kg, 6 months or more, Mas)
实验操作：Experimental operation:
以标准方案测试化合物静脉注射给药后的啮齿类动物药代特征，实验中候选化合物配成澄清溶液，给予比格犬单次静脉注射给药1mg/kg。静注溶媒为10％羟丙基β环糊***溶液。分别在0.033、0.083、0.25、0.5、1、2、4、8、12、2424小时采集全血，3000r离心10分钟，分离上清得血浆样品，20μL血浆样品和400μL含有内标的乙腈溶液沉淀蛋白混合，离心取上清液2μL进样，以LC-MS/MS分析方法定量分析血药浓度，并计算药代参数，如清除率，半衰期，药时曲线下面积等。The rodent pharmacokinetic characteristics of the compound after intravenous injection were tested in a standard protocol. In the experiment, the candidate compound was formulated as a clear solution, and the beagle dog was given a single intravenous injection of 1 mg/kg. The intravenous injection solvent is 10% hydroxypropyl β cyclodextrin aqueous solution. Collect whole blood at 0.033, 0.083, 0.25, 0.5, 1, 2, 4, 8, 12, 2424 hours, centrifuge at 3000r for 10 minutes, separate the supernatant to obtain plasma samples, 20μL plasma samples and 400μL acetonitrile solution containing internal standard to precipitate protein Mix, centrifuge and take 2μL of supernatant for injection, quantitatively analyze the blood drug concentration by LC-MS/MS analysis method, and calculate the pharmacokinetic parameters, such as clearance rate, half-life, area under the curve of drug time, etc.
实验结果：Experimental results:
表5 药代动力学测试结果Table 5 Pharmacokinetic test results
Figure PCTCN2019126178-appb-000067
Figure PCTCN2019126178-appb-000067
Figure PCTCN2019126178-appb-000068
Figure PCTCN2019126178-appb-000068
结论：本发明清除率高，半衰期适中，有良好的药代动力学特征。Conclusion: The present invention has high clearance rate, moderate half-life, and good pharmacokinetic characteristics.
三、three,
实验目的：测试化合物在食蟹猴体内药代动力学研究Experimental purpose: Pharmacokinetic study of test compounds in cynomolgus monkeys
实验材料：食蟹猴(雄性，2.5-4kg,大于等于2年，海南金港)Experimental material: Crab-eating monkey (male, 2.5-4kg, greater than or equal to 2 years, Hainan Golden Port)
实验操作：Experimental operation:
以标准方案测试化合物静脉注射给药后在猴子内的药代特征，实验中候选化合物配成澄清溶液，给予食蟹猴单次静脉注射给药1mg/kg。静注溶媒为10％羟丙基β环糊***溶液。分别在0.033、0.083、0.25、0.5、1、2、4、8、12、24小时采集全血，3000r离心10分钟，分离上清得血浆样品，20μL血浆样品和400μL含有内标的乙腈溶液沉淀蛋白混合，离心取上清液2μL进样，以LC-MS/MS分析方法定量分析血药浓度，并计算药代参数，如清除率，半衰期，药时曲线下面积等。The standard protocol was used to test the pharmacokinetic characteristics of the compound in the monkey after intravenous injection. In the experiment, the candidate compound was formulated as a clear solution, and the cynomolgus monkey was given a single intravenous injection of 1 mg/kg. The intravenous injection solvent is 10% hydroxypropyl β cyclodextrin aqueous solution. Whole blood was collected at 0.033, 0.083, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours, centrifuged at 3000r for 10 minutes, and the supernatant was separated into plasma samples, 20 μL of plasma sample and 400 μL of acetonitrile solution containing internal standard to precipitate protein Mix, centrifuge and take 2μL of supernatant for injection, quantitatively analyze the blood drug concentration by LC-MS/MS analysis method, and calculate the pharmacokinetic parameters, such as clearance rate, half-life, area under the curve of drug time, etc.
实验结果：Experimental results:
表6 药代动力学测试结果Table 6 Pharmacokinetic test results
Figure PCTCN2019126178-appb-000069
Figure PCTCN2019126178-appb-000069
结论：本发明清除率高，半衰期适中，有良好的药代动力学特征。Conclusion: The present invention has high clearance rate, moderate half-life, and good pharmacokinetic characteristics.
实验例4：体内药动学性质研究Experimental Example 4: Study on pharmacokinetic properties in vivo
实验目的：大鼠滴眼给药后角膜与血浆药物浓度比例The purpose of the experiment: the ratio of corneal to plasma drug concentration after eye drop administration in rats
实验材料：雄性SD大鼠，200-300g,7～9周龄，上海灵畅Experimental material: male SD rat, 200-300g, 7-9 weeks old, Shanghai Lingchang
实验操作：将候选化合物配置成澄清溶液，给予SD大鼠滴眼给药。滴眼的溶媒为10％羟丙基β环糊***溶液，滴眼液药物浓度为5mg/mL。分别在1和4小时采集角膜和全血。角膜使用15mM磷酸缓冲液(PBS):MeoH(2:1,v:v)缓冲液进行匀浆，全血样品在3000r离心10分钟，分离上清的血浆样品。20μL血浆样品和匀浆液样品分别和400μL含有内标的乙腈的溶液沉淀蛋白混合，离心取上清液2μL进样，以LC-MS/MS分析方法定量分析血药浓度并根据不同的时间点，分别检测角膜和血浆中的药物浓度，计算角膜/血浆比。Experimental operation: The candidate compound was formulated as a clear solution and administered to SD rats by eye drops. The vehicle for eye drops is a 10% hydroxypropyl β cyclodextrin aqueous solution, and the drug concentration for eye drops is 5 mg/mL. Corneal and whole blood were collected at 1 and 4 hours, respectively. The cornea was homogenized with 15mM phosphate buffer (PBS): MeoH (2:1, v:v) buffer, and the whole blood sample was centrifuged at 3000r for 10 minutes to separate the supernatant plasma sample. 20 μL of plasma sample and homogenate sample were mixed with 400 μL of acetonitrile solution containing internal standard to precipitate protein, centrifuge to take 2 μL of supernatant for injection, and quantitative analysis of blood drug concentration by LC-MS/MS analysis method and according to different time points, respectively The drug concentration in the cornea and plasma was measured, and the cornea/plasma ratio was calculated.
实验结果：Experimental results:
表7 药代动力学测试结果Table 7 Pharmacokinetic test results
Figure PCTCN2019126178-appb-000070
Figure PCTCN2019126178-appb-000070
结论：通过DMPK试验，可以看到测试化合物3，7，8通过滴眼给药能进入角膜，起药效作用，化合物3的角膜/血浆比较高，比例大于10，药效作用在角膜，靶向性好。Conclusion: Through the DMPK test, it can be seen that the test compounds 3, 7, 8 can enter the cornea by eye drop administration and have a drug effect. The cornea/plasma of compound 3 is relatively high, the ratio is greater than 10, and the drug effect is on the cornea and target Good tropism.
实验例5：体内药效评价Experimental Example 5: Evaluation of in vivo drug efficacy
试验目的：Test purposes:
皮下注射东莨菪碱可诱导的小鼠干眼症，通过泪液测试及角膜荧光染色评分检查可看出泪液分泌减少及炎症浸润。并且在造模初期可预测模型是否能达到预期的严重程度。Subcutaneous injection of scopolamine can induce dry eye syndrome in mice, and tear tear test and corneal fluorescence staining score examination can show reduced tear secretion and inflammation infiltration. And in the early stage of modeling, it can be predicted whether the model can reach the expected severity.
试验设计：Test design:
· 从25只雌性C57BL/6J小鼠中选择20只动物，按体重通过Provantis或Excel随机化分入4组，每组4只动物，分组也将参考试验前各动物泪液测试和角膜荧光染色评分结果。· Select 20 animals from 25 female C57BL/6J mice, and divide them into 4 groups according to body weight by Provantis or Excel randomization, each group of 4 animals, the group will also refer to the tear test and corneal fluorescence staining score of each animal before the test result.
· 试验第1～12天，每天4次皮下注射氢溴酸东莨菪碱(3±0.5h)进行小鼠干眼症造模，0.1mL/只/次。· On the 1st to 12th days of the test, scopolamine hydrobromide (3±0.5h) was injected subcutaneously 4 times a day to model dry eye in mice, 0.1mL/piece/time.
· 试验第1～13天，每天对动物进行4次双眼滴眼给药(3±0.5h)，3μL/眼(Day 13，第1组不给药)。· From the 1st to the 13th day of the test, the animals were given eye drops (3±0.5h) 4 times a day, 3μL/eye (Day 13, no dose in group 1).
每次皮下注射氢溴酸东莨菪碱都需在滴眼给药前(Day 7和Day 12检查除外)。Each subcutaneous injection of scopolamine hydrobromide needs to be administered before eye drops (except for Day 7 and Day 12 examinations).
在造模前，Day 7和Day 12对所有实验动物进行泪液测试，角膜荧光染色评分。Before modeling, Day 7 and Day 12 performed tear test on all experimental animals and scored corneal fluorescence staining.
角膜荧光染色评分标准：将动物角膜分为5个区域，分别为上，下，鼻侧，颞侧以及中央区域，每个区域都是0～3分，对每个区域进行评分，单眼分数为五个区域分数的总和。0分，无着染；1分，轻微着染，点状着染且数量少于5；2分，中度着染，点状着染但无斑块性着染；3分，重度着染，明显荧光斑块。Corneal fluorescent staining scoring standard: the animal cornea is divided into 5 regions, namely, upper, lower, nasal, temporal and central regions, each region is 0 to 3 points, each region is scored, the single eye score is The sum of the five regional scores. 0 points, no staining; 1 point, slight staining, dot-like staining and less than 5; 2 points, moderate staining, dot-like staining but no patchy staining; 3 points, heavy staining , Obvious fluorescent plaque.
Day 7和Day 12对所有实验动物的泪液测试检查在第二次给药后30分钟进行，Day 7和Day 12对所有实验动物的角膜荧光染色评分检查需在第三次给药后30分钟进行。Day 7 and Day 12 tear test tests for all laboratory animals are performed 30 minutes after the second administration, and Day 7 and Day 12 test corneal fluorescence staining scores for all laboratory animals must be performed 30 minutes after the third administration .
表8 小鼠皮下注射东莨菪碱药效实验方案Table 8 Experimental scheme of scopolamine subcutaneous injection in mice
Figure PCTCN2019126178-appb-000071
Figure PCTCN2019126178-appb-000071
试验结果：见图2和图3(注：附图中*表示P≤0.5，**biaos P≤0.01，***表示P≤0.001)。Test results: See Figure 2 and Figure 3 (Note: in the drawings * indicates P≤0.5, **biaos P≤0.01, *** indicates P≤0.001).
结论：在本实验条件下，可以看到所有测试化合物均可改善泪液分泌和角膜炎症，呈现出改善干眼症药效作用。Conclusion: Under the conditions of this experiment, it can be seen that all the test compounds can improve tear secretion and corneal inflammation, showing the effect of improving dry eye.

Claims (12)

  1. 式(II)所示化合物或其药学上可接受的盐，A compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2019126178-appb-100001
    Figure PCTCN2019126178-appb-100001
    其中，among them,
    Figure PCTCN2019126178-appb-100002
    选自单键和双键；
    Figure PCTCN2019126178-appb-100002
    Choose from single and double bonds;
    T 1、T 2、T 3和T 4分别独立地选自N、C和CR 1； T 1 , T 2 , T 3 and T 4 are independently selected from N, C and CR 1 ;
    T 5选自C、CR 5和C＝O； T 5 is selected from C, CR 5 and C=O;
    T 6选自C、CR 6和N； T 6 is selected from C, CR 6 and N;
    T 7选自N和CR 7； T 7 is selected from N and CR 7 ;
    当T 5选自C＝O，T 6选自N时，
    Figure PCTCN2019126178-appb-100003
    选自单键；     When T 5 is selected from C=O and T 6 is selected from N,
    Figure PCTCN2019126178-appb-100003
    Selected from single bonds;
    L选自单键、-O-、-S-、-NR 2-和-(CR 3R 4) n-； L is selected from single bonds, -O-, -S-, -NR 2 -and -(CR 3 R 4 ) n -;
    各R 1分别独立地选自H、F、Cl、Br、I、OH和NH 2； Each R 1 is independently selected from H, F, Cl, Br, I, OH, and NH 2 ;
    R 2选自H和任选被1、2或3个R a取代的C 1-3烷基； R 2 is selected from H and optionally substituted with 1,2 or 3 substituents R a is C 1-3 alkyl;
    R 3和R 4分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和任选被1、2或3个R b取代的C 1-3烷基； R 3 and R 4 are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2, or 3 R b ;
    R 5、R 6和R 7分别独立地选自H、F、Cl、Br和I； R 5 , R 6 and R 7 are independently selected from H, F, Cl, Br and I;
    n选自1、2和3；n is selected from 1, 2, and 3;
    R a和R b分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和CH 3。 R a and R b are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and CH 3 .
  2. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 2选自H、CH 3和CH 2CH 3，所述CH 3和CH 2CH 3任选被1、2或3个R a取代。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from H, CH 3 and CH 2 CH 3 , and the CH 3 and CH 2 CH 3 are optionally selected from 1, 2 or 3 R a is substituted.
  3. 根据权利要求2所述化合物或其药学上可接受的盐，其中，R 2选自H、CH 3和CH 2CH 3。 The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from H, CH 3 and CH 2 CH 3 .
  4. 根据权利要求1～3任意一项所述化合物或其药学上可接受的盐，其中，R 3和R 4分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3和CH 2CH 3，所述CH 3和CH 2CH 3任选被1、2或3个R b取代。 The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 and CH 2 CH 3 , the CH 3 and CH 2 CH 3 are optionally substituted with 1, 2 or 3 R b .
  5. 根据权利要求4所述化合物或其药学上可接受的盐，其中，R 3和R 4分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3和CH 2CH 3。 The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 and CH 2 CH 3 .
  6. 根据权利要求5所述化合物或其药学上可接受的盐，其中，L选自单键、-O-、-S-、-NH-、-(CH 2) 2-和-CH 2-。 The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein L is selected from a single bond, -O-, -S-, -NH-, -(CH 2 ) 2 -, and -CH 2 -.
  7. 根据权利要求1～6任意一项所述化合物或其药学上可接受的盐，其选自The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, which is selected from
    Figure PCTCN2019126178-appb-100004
    Figure PCTCN2019126178-appb-100004
    其中，among them,
    T 3、T 4分别独立地选自N和CR 1； T 3 and T 4 are independently selected from N and CR 1 ;
    R 1和L如权利要求1～6任意一项所定义。 R 1 and L are as defined in any one of claims 1 to 6.
  8. 根据权利要求7所述化合物或其药学上可接受的盐，其选自The compound according to claim 7 or a pharmaceutically acceptable salt thereof, which is selected from
    Figure PCTCN2019126178-appb-100005
    Figure PCTCN2019126178-appb-100005
    其中，among them,
    R 1和L如权利要求7所定义。 R 1 and L are as defined in claim 7.
  9. 下式所示化合物或其药学上可接受的盐，其选自：The compound represented by the following formula or a pharmaceutically acceptable salt thereof is selected from:
    Figure PCTCN2019126178-appb-100006
    Figure PCTCN2019126178-appb-100006
  10. 一种药物组合物，包括作为活性成分的治疗有效量的根据权利要求1～9任意一项所述的化合物或其药学上可接受的盐以及药学上可接受的载体。A pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  11. 根据权利要求1～9任意一项所述的化合物或其药学上可接受的盐或者权利要求10的组合物在制备醛结合剂相关药物上的应用。Use of the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof or the composition of claim 10 in the preparation of a drug related to an aldehyde binder.
  12. 根据权利要求11所述的应用，其特征在于，所述醛结合剂相关药物是用于干眼症的药物。The use according to claim 11, characterized in that the aldehyde-binding agent-related drug is a drug for dry eye.
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